Tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds

ABSTRACT

Compounds of the general formula I:   &lt;IMAGE&gt;   are disclosed as useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Novel intermediate compounds used to make the compound of formula I are also disclosed.

This is a division, of application Ser. No. 886,569, filed May 20, 1992 now U.S. Pat. No. 5,250,561, which is hereby incorporated by reference, which is a divisional of Ser. No. 742,788, filed Aug. 8, 1991, now U.S. Pat. No. 5,134,155.

BACKGROUND OF THE INVENTION

Compounds which inhibit HMG-CoA reductase, the enzyme controlling the rate-limiting step in cholesterol biosynthesis, are assuming an important role in the management of certain forms of hyperlipidemia. Lovastatin, disclosed in U.S. Pat. No. 4,231,938, has been approved for use in the treatment of primary hypercholesterolemia, a disease characterized by normal serum triglyceride levels and elevated serum levels of low density lipoprotein (LDL) cholesterol and total cholesterol. In several large clinical studies, lovastatin was found to decrease plasma LDL and total cholesterol concentrations 25% to 40% while causing small but significant increases (up to 10%) in high density lipoprotein (HDL) cholesterol concentration. When compared with cholestyramine and probucol, two drugs used in the treatment of primary hypercholesterolemia, lovastatin reduced LDL cholesterol levels to a significantly greater extent. In addition, combined administration of lovastatin with other hypolipidemic agents was found to potentiate their effects on LDL and total cholesterol concentrations.

The biochemical target for lovastatin is HMG-CoA reductase, the enzyme which catalyzes the reduction of HMG-CoA to mevalonic acid. Lovastatin, in its open dihydroxy acid form, is a reversible, competitive inhibitor of the enzyme. A number of compounds structurally related to lovastatin have been shown to be inhibitors of HMG-CoA reductase. These include simvastatin (U.S. Pat. No. 4,444,784 and related compounds disclosed in U.S. Pat. No. 4,444,784). Sankyo has reported a related compound, pravastatin (U.S. Pat. No. 4,346,227). Sandoz has reported a number of HMG-CoA reductase inhibitors: indoles (U.S. Pat. No. 4,739,073), pyrazoles (U.S. Pat. No. 4,613,610), imidazoles (U.S. Pat. No. 4,808,607), and pyrazolopyridines (U.S. Pat. No. 4,822,799). Merck disclosed biphenyl-containing inhibitors in U.S. Pat. No. 4,375,475. Hoechst AG disclosed non-heterocyclic HMG-CoA reductase inhibitors in Tetrahedron Letters, 1988, 29, 929. Bristol-Myers reported tetrazole-containing compounds in UK Patent 2,202,846. Acylpyrroles are reported in U.S. Pat. No. 4,681,893 by Warner-Lambert. Warner-Lambert also disclosed pyrimidines in U.S. Pat. No. 4,868,185 and quinolines in U.S. Pat. No. 4,761,419. Bayer AG reported tri-arylpyrroles in European Patent 287,890. Rorer reported aryl-cycloalkene and aryl-cycloalkadiene inhibitors in U.S. Pat. Nos. 4,892,884 and 4,900,754. Squibb reported a number of potent compounds based on a variety of heterocycles in Journal of Medicinal Chemistry, 1990, 33, 2852. Finally, Upjohn disclosed in WO 867,357 an anti-inflammatory, anti-allergic compound generically described as cyclopentapyrazole.

The compounds of the present invention are structurally different from the known compounds and have been shown to be potent inhibitors of HMG-CoA reductase and cholesterol biosynthesis.

SUMMARY OF THE INVENTION

Novel tetrahydroindazole, tetrahydrocyclopentapyrazole, and hexahydrocycloheptapyrazole compounds of the general formula I: ##STR2## wherein R₁, R₂, R₃, Y, Z, n, and p are defined hereinafter have been found to be potent compounds for inhibiting HMG-CoA reductase and cholesterol biosynthesis and are thus useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the following general formula I: ##STR3##

R₁ is selected from any one of H, C₁ -C₈ alkyl, aryl, or substituted aryl. The R₁ substituent may be attached either directly or indirectly to either of the ring nitrogens but not both at the same time. Two double bonds represented by the dotted line in the nitrogen containing ring are positioned accordingly depending upon the position of the R₁ substituent. Examples of suitable R₁ substituents include 4-fluorophenyl and 4-chlorophenyl.

R₂ is selected from any one of H, C₁ -C₈ alkyl, aryl, substituted aryl, aralkyl wherein the alkyl portion is C₁ -C₄, substituted aralkyl wherein the alkyl portion is C₁ -C₄, aralkenyl wherein the alkenyl portion is C₁ -C₄, or C₃ -C₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of suitable R₂ groups include H, 4-fluorobenzyl, 3-phenyl-2-propenyl, cyclohexyl, ethyl, methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-phenylbenzyl, benzyl, 4-chlorobenzyl, 4-isopropylbenzyl, 4-methoxybenzyl and 4-t-butylbenzyl.

R₃ is H.

R₂ and R₃ may be taken together to form a benzo or naphtho ring system.

Y is C₁ -C₈ alkyl or C₁ -C₈ alkenyl such as CH═CH and CH═C(CH₃).

Z is selected from any one of: ##STR4## wherein R₄ is H, C₁ -C₈ alkyl, a protonated amine of the formula HN(R₅)₃ ⁺ wherein R₅ is H or C₁ -C₈ alkyl, or a cation such as Na⁺, K⁺, Li⁺, Ca²⁺, or Mg²⁺.

The values for n are 0 to 3 and the values for p are 0 to 3.

The compounds of formula I can be generally represented by three sub-groups of compounds represented by formulas I(a), I(b), and I(c) which are set forth as follows: ##STR5## wherein R₄ is any of C₁ -C₈ alkyl, and R₁, R₂, R₃, Y, n, and p are as defined above; or ##STR6## wherein R₄ is H, a cation such as Na⁺, K⁺, Li⁺, or a protonated amine of the formula HN(R₅)₃ +, wherein R₅ is H or C₁ -C₈ alkyl, and R₁, R₂, R₃, Y, n, and p are as defined above; or ##STR7## wherein R₁, R₂, R₃, Y, n, and p are as defined above.

Also within the scope of this invention are intermediate compounds which are useful in making the compounds of formula I. The intermediate compounds are represented by the general formula X: ##STR8## wherein

R₁, n, and p are as defined above.

R₂ is selected from any one of H, C₁ -C₈ alkyl, aryl, substituted aryl, aralkyl wherein the alkyl portion is C₁ -C₄, substituted aralkyl wherein the alkyl portion is C₁ -C₄, aralkenyl wherein the alkenyl portion is C₁ -C₄, or C₃ -C₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and the like.

R₃ is H.

R₂ and R₃ may be taken together to form a benzo or naphtho ring system.

The term "aryl," as used herein alone or in combination with other terms, indicates aromatic hydrocarbon groups such as a phenyl or naphthyl group. The term "aralkyl" indicates a radical containing a lower C₁ -C₈ alkyl group substituted with an aryl radical or substituted aryl radical as defined above.

The aryl groups and the ring formed by R₂ and R₃ may be independently substituted with any of C₁ -C₈ alkyl, such as methyl, ethyl, propyl, isopropyl, t-butyl, and sec-butyl; alkoxy such as methoxy and t-butoxy; halo such as fluoro, chloro, bromo, and iodo; or nitro.

As used herein alkyl and alkoxy include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. The term "independently" is used with respect to aryl and ring substituents to indicate that when more than one of such substituents is possible such substituents may be the same or different from each other. Position 1 in the N-containing ring is the N atom adjacent to the ring fusion.

The compounds produced according to the invention include the various individual isomers as well as the racemates thereof, e.g. the isomers arising from the various attachments on the side chain Z as well as the substituents R₂ and R₃.

The compounds of formula I and intermediates of formula X may be prepared according to the following general reaction scheme, which as is apparent contains a plurality of alternative routes depending upon starting materials and the reactions carried out. ##STR9##

If desired, the substituted cyclic ketone VI may be obtained from commercial suppliers (Aldrich Chemical Co., Lancaster Synthesis Ltd., or Wiley Organics). Alternatively, compound VI may be prepared as shown in the reaction scheme by treatment of imine IV (Stork, G., Dowd, S. R. J. Am. Chem. Soc., 1963, 85, 2178-80) in an inert solvent such as THF with an appropriate base such as s-BuLi or LiN(i-Pr)₂ (LDA) at -78° to 0° C. for 15 to 45 min under N₂, followed by alkylation at 0° C. to RT (room temperature) for 16 h, followed by hydrolysis of the resulting imine with 2N HCl at RT for 5 h. Alternatively, compound VI may be prepared by treatment of the 2-carboethoxy cyclic ketone V (commercially available from Aldrich Chemical Co.) in an inert solvent such as benzene or DMF with an appropriate base such as NaH at 0° to 25° C. for 30 to 60 min under N₂, followed by alkylation at 0° C. to RT for 2 to 3 days, followed by hydrolysis of the ester and decarboxylation of the resulting acid with 6N HCl at reflux for 2 to 3 days.

Compound VI can be treated with an appropriate base, such as LDA or LiN(SiMe₃)₂, in an inert solvent, such as THF, at -78° C. to 0° C. and acylated with methyl dimethoxyacetate at 0° C. to RT for 16 h to give the diketone VII. Compound VII is dissolved in an appropriate solvent, such as EtOH, and treated with a substituted hydrazine for 16 h at RT. The resulting acetal is hydrolyzed with 1N HCl at reflux to give the aldehyde X as a separable mixture of regioisomers.

Compound X can also be prepared from compound VI by several alternate routes. Thus, compound VI is treated with pyrrolidine and acetoxyacetyl chloride to give the acetoxy methyl diketone VIII (R=Ac: Dolmazon, R. J. Heterocyclic Chem., 1982, 19, 117-121). Reaction of VIII with a substituted hydrazine in a suitable solvent, such as EtOH, from RT to reflux for 4 to 10 h gives the regioisomeric mixture of acetoxy compounds XI, which is dissolved in an alcoholic solvent such as MeOH and hydrolyzed with 1N NaOH at RT to provide the separable mixture of alcohols XII. Alternatively, the THP derivative of compound VIII (R=THP), prepared by the treatment of compound VI and ethyl (tetrahydropyranyloxy)acetate (Ireland, R. Tetrahedron Lett., 1989, 30, 919-922) in ether with a suitable base, such as NaH or NaOEt, from 0° C. to RT for 16 h, can be treated with a substituted hydrazine at reflux for 4 h, followed by hydrolysis of the THP group with 1N HCl to give the separable mixture of alcohols XII.

Alternatively, compound VI is treated with NaH and diethyl oxalate to give the 2-substituted dioxoacetate IX (Tsuboi, S. J. Org. Chem, 1987, 52, 1359-62). Treatment of compound IX in MeOH with hydrazine hydrate at RT to 60° C. for 16 h gives the 3-carboethoxy compound XIII. The separable regioisomeric mixture of esters XIV is prepared by treating compound XIII with a suitable base, such as NaH, in an inert solvent, such as DMF, at 140° C. for 15 min under N₂, followed by the addition of the alkylating agent at 140° C. The alcohol XII is prepared by reduction of the corresponding 3-carboxylate XIV with a suitable reducing agent, such as LiAlH₄, in an inert solvent, such as THF, at 0° C. to RT for 2 to 3 h under N₂. Oxidation of compound XII with either MnO₂ in an appropriate solvent, such as benzene, or pyridinium chlorochromate in an appropriate solvent, such as methylene chloride, gives the corresponding aldehyde X.

Treatment of compound X with NaH and triethyl phosphonoacetate or triethyl phosphonopropionate in an inert solvent such as THF at 0° to RT for 16 h gives the corresponding ester XV. Reduction of the ester is accomplished by treatment of XV with (i-Bu)₂ AlH in an inert solvent, such as toluene or THF, for 1 to 2 h at 0° C. under N₂ to give the alcohol XVI. Alternatively, compound XVI can be prepared from the appropriately substituted cyclic ketone VI by treatment of said ketone with a substituted hydrazine and an appropriate base, such as NaOAc, in EtOH at reflux for 3 h to give the hydrazone. The hydrazone is then treated with a suitable base, such as LDA, at -10° C. and acylated with methyl 4-tetrahydropyranyloxy-2-butenoate (Harnish, W.; Morera, E.; Ortar. G. J. Org. Chem., 1985, 50, 1990-2); the resulting intermediate is treated with 3N HCl at reflux for 15 min, followed by reaction with pyridinium p-toluenesulfonate at reflux for 8 h under N₂ to give the substituted alcohol XVI. Oxidation of alcohol XVI by treatment with MnO₂ in an appropriate solvent, such as benzene, at reflux for 3 h or with CrO₃ and pyridine in an appropriate solvent, such as methylene chloride, gives aldehyde XVII. Ethyl acetoacetate is treated with an appropriate base, such as LDA, or mixture of bases, such as NaH and nBuLi, and reacted with compound XVII at 0° to -10° C. for 1 to 2 h in an inert solvent such as THF. Reaction of the intermediate ester with Et₃ B in a solvent mixture such as 1:4 MeOH:THF at 0° C., followed by treatment with NaBH₄ at -78° C. to RT for 16 h, gives the dihydroxyheptenoate I(a).

Alternatively, compound I(a) can be prepared by the reaction of compound X with methyl 3-[(t-butyldimethylsilyl)oxy-6-(dimethoxyphosphinyl)-5-oxohexanoate XVIII (Theisen, P. D.; Heathcock, C. H. J. Org. Chem., 1988, 53, 2374-81), LiCl, and DBU in an appropriate solvent, such as acetonitrile, at RT under N₂ for 6 h to give 3-hydroxy-5-oxoheptenoate XIX. Treatment of ester XIX with Et₃ B in a solvent mixture such as 1:4 MeOH:THF at 0° to -78° C., followed by reaction with NaBH₄ at -78° C. to RT for 16 h gives the dihydroxyheptenoate I(a). Compound I(a) can be hydrolyzed with aqueous NaOH or KOH and a suitable alcoholic solvent, followed optionally by neutralization with dilute aqueous HCl and treatment with an amine base, to give the dihydroxyheptenoic acid derivative I(b). Hydrolysis of compound I(a) as described above to the crude acid, followed by treatment of said acid with an appropriate carbodiimide, such as 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate, in an inert solvent, such as methylene chloride, at 0° C. to RT for 16 h, gives the tetrahydropyranyl compound I(c).

The compounds of this invention are useful as hypocholesterolimic or hypolipidemic agents by virtue of their ability to inhibit the biosynthesis of cholesterol through the inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). The ability of the compounds of the present invention to inhibit the biosynthesis of cholesterol was measured by two different tests.

HMG-CoA Reductase Isolation And Assay

Livers were harvested from male Wistar rats (250 g) following a five day feeding with powdered chow containing 2% cholestyramine. Ammonium sulfate precipitated HMG-CoA reductase was prepared from these livers according to the method of Heller, et. al. (Heller, R. A., Shrewsbury, M. A. Journal of Biological Chemistry, 251, 1976, 3815-3822). HMG-CoA reductase activity was measured using a modification of the procedure of Edwards, et. al. (Edwards, P. A., Lemongello, D., Fogelman A. M. Journal of Lipid Research, 20, 1979, 40-46). The effects of compounds on HMG-CoA reductase activity were determined by combining the compound with the enzyme and preincubating for 10 minutes prior to addition of the substrate HMG-CoA reductase.

Cell Culture Cholesterol Biosynthesis Assay

Hep-G2 cells obtained from the American Type Culture Collection were maintained in MEM (minimal essential medium) obtained from GIBCO containing Earles salts and supplemented with 10% HI-FBS. For cholesterol biosynthesis experiments, cells were plated into T25 flasks. When the cells were 2/3 confluent, they were fed MEM containing Earles salts and delipidated serum protein (DLP) at 5 mg/mL and then incubated for a period of 24 h. DLP was prepared according to the procedure of Rothblat, et. al. (Rothblat, G. H., Arrbogast, L. Y., Ouellette, L., Howard, B. V. In Vitro (Rockville), 12, 1976, 554-557). The DLP medium was then removed and 3.3 mL of media containing the drug indicated was added. Monolayers were incubated with drug for 2.5 h at which time ¹⁴ C-acetate (0.2 mCi/12 mmol) was added and cells incubated for an additional 3 h. The reaction was stopped by the addition of 0.2 mL of 12N H₂ SO₄ ; ³ H-cholesterol and ³ H-oleic acid were added as internal recovery standards, and samples were saponified. Fatty acids were extracted and digitonin precipitable sterols were recovered according the procedure of Kanduch and Saucier (Kandutch. A. A., Saucier, S. E. Journal of Biological Chemistry, 244, 1969, 2299-2305). To adjust for cell number per flask, the cholesterol synthesized was normalized to the fatty acids synthesized and results were expressed as percent inhibition vs. control.

The activities of certain representative examples are shown in Tables I-V. In the Tables, Me means methyl, Et is ethyl, Pr is propyl, Bu is butyl, c-Hex is cyclohexyl, Ph is phenyl, Nap is naphthyl, MeO is methoxy, and Biphenyl is (1,1'-biphenyl)-4-yl. Each of the compounds was tested in the form of a racemic mixture.

Each of the compounds in Tables I-V was tested in one or both of the biological assays. The symbol "nt" indicates that a particular compound was not tested.

                  TABLE I                                                          ______________________________________                                          ##STR10##                                                                     Compound                Cell Culture Cholesterol                               Number   R.sub.2        Biosynthesis IC.sub.50 (μM)                         ______________________________________                                         42       (2-Nap)CH.sub.2                                                                               0.365                                                  43       (4-i-PrPh)CH.sub.2                                                                            0.12                                                   ______________________________________                                    

                                      TABLE II                                     __________________________________________________________________________      ##STR11##                                                                     Compound                   HMG-CoA    Cell Culture Cholesterol                 Number                                                                               n R.sub.1 R.sub.2    Reductase IC.sub.50 (nM)                                                                  Biosynthesis IC.sub.50                   __________________________________________________________________________                                           (μM)                                  2     0 4-FPh   H          100,000    nt                                       3     1 4-FPh   (4-FPh)CH.sub.2                                                                           31,000     27                                       4     1 4-FPh   c-Hex      47,000     nt                                       5     1 4-FPh   Et         35,000     nt                                       6     1 4-FPh   Me         100,000    nt                                       7     1 4-FPh   Ph(CH.sub.2).sub.2                                                                        nt         >10                                      8     1 4-FPh   PhCHCHCH.sub.2                                                                             3,000     nt                                       9     2 (4-FPh)CH.sub.2                                                                        H          100,000    nt                                       __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________      ##STR12##                                                                     Compound                                HMG-CoA    Cell Culture                                                                   Cholesterol                 Number                                                                               n  R.sub.1  R.sub.2      R.sub.3                                                                          Y      Reductase IC.sub.50                                                                       Biosynthesis IC.sub.50                                                         (μM)                     __________________________________________________________________________      1    1  4-FPh    (Biphenyl)-CH.sub.2                                                                         H CHCH   2.7        0.24                        10    0  4-FPh    H            H CHCH   5,100      nt                          11    1  4-FPh    (1-Nap)CH.sub.2                                                                             H CHCH     26       0.37                        12    1  4-FPh    (2-ClPh)CH.sub.2                                                                            H CHCH     100      1.3                         13    1  4-FPh    (2-Nap)CH.sub.2                                                                             H CHCH   5.6        0.33                        14    1  4-FPh    (3-MeOPh)CH.sub.2                                                                           H CHCH     48       1.09                        15    1  4-FPh    (3,4-di-MeOPh)CH.sub.2                                                                      H CHCH     168      3.9                         16    1  4-FPh    (4-ClPh)CH.sub.2                                                                            H CHCH     58       0.36                        17    1  4-FPh    (4-FPh)CH.sub.2                                                                             H CHCH     150      0.70                        18    1  4-FPh    (4-i-PrPh)CH.sub.2                                                                          H CHCH     14       0.26                        19    1  4-FPh    (4-MePh)CH.sub.2                                                                            H CHCH     19       0.13                        20    1  4-FPh    (4-MeOPh)CH.sub.2                                                                           H CHCH     14       0.46                        21    1  4-FPh    (4-t-BuPh)CH.sub.2                                                                          H CHCH     16       0.135                       22    1  4-FPh    6,7-Benzo      CHCH   13,000     nt                          23    1  4-FPh    c-Hex        H CHCH   7,700      nt                          24    1  4-FPh    Et           H CHCH   1,000      nt                          25    1  4-FPh    H            H CHCH   2,500      nt                          26    1  4-ClPh   H            H CHCH   8,800      nt                          27    1  4-FPh    H            H CHC(Me)                                                                               2,700      nt                          28    1  4-FPh    Me           H CHCH   1,100      nt                          29    1  4-FPh    n-Pr         H CHCH   1,300      nt                          30    1  4-FPh    Ph           H CHCH   3,100      nt                          31    1  4-FPh    PhCH.sub.2   H CHCH     85       0.22                        32    1  4-FPh    Ph(CH.sub.2).sub.2                                                                          H CHCH     334      1.75                        33    1  4-FPh    Ph(CH.sub.2).sub.3                                                                          H CHCH     160      1.1                         34    1  4-FPh    PhCHCHCH.sub.2                                                                              H CHCH     32       1.3                         35    1  4-FPh    s-Bu         H CHCH   1,000      nt                          36    2  4-FPh    7,8-Benzo      CHCH   2,100      nt                          37    2  4-FPh    H            H CHCH   3,800      nt                          38    2  (4-FPh)CH.sub.2                                                                         H            H CHCH   23,000     nt                          __________________________________________________________________________

                  TABLE IV                                                         ______________________________________                                          ##STR13##                                                                                                       Cell Culture                                                        HMG-CoA    Cholesterol                                  Compound               Reductase  Biosynthesis                                 Number  R.sub.2        IC.sub.50 (nM)                                                                            IC.sub.50 (μM)                            ______________________________________                                         47      PhCH.sub.2     120        0.29                                         58      (3-MeOPh)CH.sub.2                                                                             210        0.80                                         60      (4-ClPh)CH.sub.2                                                                              nt         0.46                                         62      (4-MePh)CH.sub.2                                                                               70        0.20                                         64      (4-t-BuPh)CH.sub.2                                                                             30        nt                                           ______________________________________                                    

                  TABLE V                                                          ______________________________________                                          ##STR14##                                                                                                       Cell Culture                                                        HMG-CoA    Cholesterol                                  Compound               Reductase  Biosynthesis                                 Number   R.sub.2       IC.sub.50 (nM)                                                                            IC.sub.50 (μM)                            ______________________________________                                         79       PhCH.sub.2      750      0.26                                         80       (2-Et)Bu      29,000     nt                                           81       (2-Nap)CH.sub.2                                                                              nt         0.39                                         82       (4-t-BuPh)CH.sub.2                                                                             70       0.23                                         83       H             9,000      nt                                           ______________________________________                                    

The pharmaceutical compositions containing compounds of the present invention are comprised of the compounds of the present invention and a pharmaceutically acceptable carrier in either solid or liquid form. Solid form preparations include powders, tablets, dispersible granules, capsules, etc. The carrier may also be one or more substances which act as diluents, flavoring agents, solublizers, lubricants, suspending agents, binders, or tablet disintegrating agents and they may also be encapsulating materials. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methyl cellulose, sodium carboxyl methyl cellulose, and the like. Liquid form preparations include solutions which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active components in solvents comprising water, ethanol, or propylene glycol are examples of liquid preparations suitable for parenteral administration. Sterile solutions may be prepared by dissolving the active component in the desired solvent system, then passing the resulting solution through a membrane filter to sterilize it, or alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions. Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as a natural or synthetic gum, resin methyl cellulose, sodium carboxy methyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form" as used in the specification and claims herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

In therapeutic use as hypolipidemic or hypochloesterolemic agents, the compounds utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels of from about 0.01-100 mg/kg per day. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.

In the following examples, Examples 13, 14, 20 and 21, Tables 8, 9A, 9B, 13A, 13B, and 14, illustrate the preparation of the final compounds I(a-c) according to the present invention. Examples 3 and 11, Tables 3A, 3B, and 6, illustrate the preparation of the novel intermediate of the compound of formula X. The remainder of the examples illustrate the preparations of the various intermediates according to the reaction scheme set forth previously that are made to produce the compounds of the present invention. For ease of reference, each example is keyed to a particular step in the reaction scheme. Moreover, there are specific examples of one compound for each step in the sequence and a general procedure for making the other compounds which are listed in the table at the end of each example.

Unless otherwise noted, materials used in the examples were obtained from commercial suppliers and were used without further purification. Tetrahydrofuran (THF) was distilled from Na/benzophenone immediately prior to use. The following chemicals were obtained from Sigma Chemical Co: digitonin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH). The (1-¹⁴ C)-acetate was obtained from both Research Biochemicals, Inc. (RBI) and New England Nuclear-Dupont (NEN). The (3-¹⁴ C)-HMG-CoA was obtained from NEN, and (7-³ H)-cholesterol and (7-³ H)-cholesteryl oleate were obtained from Amersham. HI-FBS (heat-inactivated fetal bovine serum) and calf serum were obtained from Grand Island Biological Co. (GIBCO). Lovastatin was obtained from Merck. Lovastatin-Na was prepared from Lovastatin by reaction with sodium hydroxide. Pravastatin was obtained from Sigma, and XU-62320 was obtained from Sandoz. Diisopropylamine was distilled from CaH₂ and was stored over 4A molecular sieves. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used without purification. Dimethylformamide (DMF) was dried over 4A sieves prior to use. Melting points were determined on a Thomas-Hoover apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard using the following spectrometers: Bruker WP-100SY (100 MHz ¹ H, 25 MHz ¹³ C), General Electric QE-300 (300 MHz ¹ H, 75 MHz ¹³ C), Varian XL-400 (400 MHz ¹ H, 100 MHz ¹³ C). NMR chemical shifts are expressed in parts per million (ppm) downfield from internal TMS using the δ scale. ¹ H Hertz). ¹³ C NMR data are reported for proton-decoupled spectra and are tabulated in order. Infrared (IR) spectra were determined on a Nicolet 5DXB FT-IR spectrophotometer. Chemical ionization (DCI), electron impact (EI), and fast atom bombardment (FAB) mass spectra (MS) were determined on a Finnegan MAT 8230 spectrometer. Elemental analyses were carried out on a Perkin Elmer 240C analyzer. Analytical thin layer chromatography (TLC) was done with Merck Silica Gel 60 F₂₅₄ plates (250 micron). Flash chromatography and medium pressure liquid chromatography (MPLC) were done with Merck Silica Gel 60 (230-400 mesh).

EXAMPLE 1 2-[(1,1'-Biphenyl)-4-ylmethyl]cyclohexanone (Compound(hereinafter CP) 84, Reaction Scheme(hereinafter RS)Step a)

A 1.3M solution of s-BuLi in hexanes (51.8 mmol, 39.8 mL) was added over a 15 min period to a -78° C. solution containing 9.29 g (51.8 mmol) of N-cyclohexylidine cyclohexylamine (Stork, G., Dowd, S. R. J. Am. Chem. Soc., 1963, 85, 2178-80) in 75 mL of THF under N₂. After 30 min, the cooling bath was removed and the cloudy solution was allowed to warm to 0° C. A solution of 10.0 g (49.3 mmol) of 4-(chloromethyl)biphenyl in 30 mL of THF was added and the resulting mixture was stirred at room temperature overnight. A 40 mL portion of 2N aqueous HCl was added and the mixture was stirred for 5 h. Et₂ O (200 mL) was added and the organic solution was washed successively with water, saturated NaHCO₃, and brine. The organic layer was dried over Na₂ SO₄ and concentrated to give 13.1 g of an off-white solid. Recrystallization from EtOAc:hexanes afforded 9.22 g (71%) of the title compound as a white solid, m.p. 78°-79° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.40 (m, 1), 1.65 (m, 2), 1.83 (m, 1), 2.10 (m, 2), 2.35 (m, 1), 2.52 (m, 2), 2.60 (m, 1), 3.27 (dd, 1, J=5, 13.5 Hz), 7.2-7.6 (complex); IR (KBr) 1695 cm⁻¹ ; MS (DCI) m/z 265 (base). Anal. Calcd. for C₁₉ H₂₀ O: C, 86.32; H, 7.63. Found: C, 86.66; H, 7.98.

General procedure for the preparation of 2-substituted cyclohexanones shown in Table 1:

Method A (RS step a): s-BuLi (50 mmol) was added under N₂ to a solution of 50 mmol of the cyclohexylimine of N-cyclohexylidine cyclohexylamine in 75 mL of THF at -78° C. The resulting cloudy solution was stirred for 30 min and was allowed to warm to 0° C. A solution of 48 mmol of the appropriate alkyl or aralkyl halide in a minimum volume of THF was added dropwise and the solution was allowed to warm to room temperature and was stirred overnight. A 50 mL portion of 2N aqueous HCl (100 mmol) was added and the two phase mixture was stirred vigorously until TLC analysis showed that hydrolysis of the imine was complete (2-8 h). The mixture was extracted with Et₂ O or EtOAc and the organic layer was washed with water, saturated aqueous NaHCO₃, and brine. After drying over Na₂ SO₄ and concentration, the crude product was purified by either MPLC or vacuum distillation using a short path still.

Alternatively, a solution of 50 mmol of the appropriate cyclohexylimine in a minimum volume of THF was added dropwise under N₂ to an ice-cold stirring solution of 52.5 mmol of lithium diisopropylamide (LDA, generated by the addition of 55 mmol of diisopropylamine in 35 mL of THF to 52.5 mmol of a 1.6M hexanes solution of n-BuLi at 0° C.). After 30-45 min, a solution of 48 mmol of the appropriate alkyl or aralkyl halide in a minimum volume of THF was added dropwise and the mixture was allowed to warm to room temperature and was stirred overnight. A 75 mL portion of 2N aqueous HCl (150 mmol) was added and the two phase mixture was stirred vigorously until TLC analysis showed that hydrolysis of the imine was complete (4-24 h). The reaction mixture was worked up as described above.

Method B (RS step b): An ice-cold suspension of oil-free NaH (150 mmol) in 120 mL of a 1:1 mixture of benzene and DMF was treated, dropwise, with ethyl 2-cyclohexanonecarboxylate (145 mmol) in 60 mL of the same solvent mixture over a 30 min period. The mixture was stirred an additional 30 min and 140 mmol of the appropriate alkyl or aralkyl halide in a minimum amount of benzene was added dropwise. After stirring at room temperature for 2-3 days, 250 mL of Et₂ O was added and the organic solution was washed with water (3×100 mL) and brine. Drying (Na₂ SO₄) and concentration gave the crude alkylated keto ester which was dissolved in 100 mL each of HOAc and 6N aqueous HCl and refluxed until TLC analysis showed that the hydrolysis/decarboxylation was complete (2-3 days). Most of the solvent was removed by rotary evaporation and the residue was partitioned between water (100 mL) and Et₂ O (300 mL). The Et₂ O layer was washed with brine, dried over Na₂ SO₄, and concentrated to give the crude product which was purified as described in Method A above.

                                      TABLE 1                                      __________________________________________________________________________      ##STR15##                                                                     Compound                         Mass spectrum                                 Number                                                                               Method                                                                              R.sub.2      bp (°C.)                                                                         m/z [M + H].sup.+                             __________________________________________________________________________     85    A    (1-Nap)CH.sub.2                                                                             oil      239                                           86    B    (2-ClPh)CH.sub.2                                                                            129-135 (0.4 Torr)                                                                      223                                           87    A    (2-Nap)CH.sub.2                                                                             180-190 (0.6 Torr)                                                                      239                                           88    A    (3-MeOPh)CH.sub.2                                                                           190-195 (4 Torr)                                                                        219                                           89    A    (3,4-di-MeOPh)CH.sub.2                                                                      180-187 (1 Torr)                                                                        249                                           90    A    (4-ClPh)CH.sub.2                                                                            150-170 (0.1 Torr)                                                                      223                                           91    B    (4-FPh)CH.sub.2                                                                             110-125 (0.5 Torr)                                                                      207                                           92    A    (4-i-PrPh)CH.sub.2                                                                           90-160 (0.1 Torr)                                                                      231                                           93    A    (4-MePh)CH.sub.2                                                                            oil      203                                           94    B    (4-MeOPh)CH.sub.2                                                                           155-170 (0.6 Torr)                                                                      219                                           95    A    (4-t-BuPh)CH.sub.2                                                                          135-148 (0.5 Torr)                                                                      245                                           96    A    Ph(CH.sub.2).sub.2                                                                          124-130 (0.5 Torr)                                                                      203                                           97    A    Ph(CH.sub.2).sub.3                                                                          100-200 (0.8 Torr)                                                                      217                                           98    A    PhCHCHCH.sub.2                                                                              160- 170 (0.8 Torr)                                                                     215                                           __________________________________________________________________________

EXAMPLE 2 6-[(1,1'-Biphenyl-4-yl)methyl]-2-(2,2-dimethoxy-1-oxoethyl)cyclohexanone (CP 99, RS step c)

Diisopropylamine (38.8 mmol, 3.93 g, 5.4 mL) was added under N₂ to a -20° C. solution of 1.6M n-BuLi in hexanes (35.3 mmol, 22.0mL) and 30 mL of THF. After 15 min, the solution was cooled to -78° C. and 8.88 g (33.6 mmol) of Compound 84 in 50 mL of THF was added. After 45 min, 2.26 mL (18.5 mmol, 2.48 g) of methyl dimethoxyacetate was added and the mixture was allowed to warm slowly to room temperature and was stirred overnight. The resulting solution was cooled to 0° C. and acidified to pH 3-4 with 2N aqueous HCl. The mixture was diluted with Et₂ O (200 mL) and washed with water and brine. After drying over Na₂ SO₄, the solution was concentrated to give 11.5 g of a yellow oil. The crude product was purified by MPLC using a solvent gradient ranging from 1:6 to 1:5 EtOAc:hexanes to afford 5.94 g (96%) of the title compound as a waxy, white solid; ¹ H NMR (CDCl₃, 300 MHz) 1.4-2.8 (complex, 9), 3.33 (s, 3, minor tautomer), 3.37 (s, 3, minor tautomer), 3.42 (s, 6, major tautomer), 4.63 (s, 1, minor tautomer), 4.96 (s, 1, major tautomer), 7.2-7.6 (complex, 9); IR (KBr) 1739, 1704, 1601, 1584, 1488, 1444 cm⁻¹ ; MS (DCI) m/z 335 (base), 303. Anal. Calcd. for C₂₃ H₂₆ O₄ : C, 75.38; H, 7.15. Found: C, 75.64; H, 7.39.

General procedure for the preparation of 6-substituted diketones shown in Table 2 (RS step c):

Diisopropylamine (57.8 mmol) was added under N₂ to a -20° C. solution of 52.5 mmol of a 1.6M hexanes solution of n-BuLi and 45 mL of THF. (Alternatively, 52.5 mmol of a 1.0M solution of LiN(SiMe₃)₂ in THF/cyclohexane was added to 25 mL of THF under N₂ at -20° C.) After 15 min, the solution was cooled to -78° C. and 50.0 mmol of the appropriately substituted cyclohexanone (from Table 1, or commercially available) in 50 mL of THF was added. After 45 min, 27.5 mmol of methyl dimethoxyacetate was added and the mixture was allowed to warm slowly to room temperature. After stirring overnight, the resulting solution was cooled to 0° C. and acidified to pH 3-4 with 2N aqueous HCl. The mixture was diluted with Et₂ O (200 mL) and washed with water and brine. After drying over Na₂ SO₄, the solution was concentrated to give the crude product, which was purified by MPLC.

                  TABLE 2                                                          ______________________________________                                          ##STR16##                                                                     Com-                                                                           pound                   mp     Mass spectrum                                   Number R.sub.2          (°C.)                                                                          m/z [MH-MeOH].sup.+                             ______________________________________                                         100    (1-Nap)CH.sub.2  oil    309                                             101    (2-ClPh)CH.sub.2 oil    293                                             102    (2-Et)Bu         oil    225                                             103    (2-Nap)CH.sub.2  oil    309                                             104    (3-MeOPh)CH.sub.2                                                                               oil    289                                             105    (3,4-di-MeOPh)CH.sub.2                                                                          oil    319                                             106    (4-ClPh)CH.sub.2 oil    293                                             107    (4-FPh)CH.sub.2  oil    277                                             108    (4-i-PrPh)CH.sub.2                                                                              oil    301                                             109    (4-Me-Ph)CH.sub.2                                                                               oil    273                                             110    (4-MeOPh)CH.sub.2                                                                               oil    289                                             111    (4-t-BuPh)CH.sub.2                                                                              oil    315                                             112    c-Hex            oil    251                                             113    Et               oil    197                                             114    Me               oil    183                                             115    n-Pr             oil    211                                             116    Ph               oil    245                                             117    PhCH.sub.2       oil    259                                             118    Ph(CH.sub.2).sub.2                                                                              oil    273                                             119    Ph(CH.sub.2).sub.3                                                                              oil    287                                             120    PhCHCHCH.sub.2   oil    285                                             121    s-Bu             oil    225                                             ______________________________________                                    

EXAMPLE 3 7-[(1,1'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxaldehyde (CP 122, RS step g) and 7-[(1,1'-Biphenyl-4-yl)methyl]-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxaldehyde (CP 123 RS step g)

A solution of Compound 99 (20.2 mmol. 5.35 g) in 100 mL of absolute EtOH was treated with 1.91 g (23.3 mmol) of NaOAc and 3.45 g (21.2 mmol) of 4-fluorophenylhydrazine • HCl. After stirring overnight under N₂, the solvent was removed by rotary evaporation and the orange residue was dissolved in 100 mL of THF. A 50 mL portion of 1N aqueous HCl was added and the mixture was stirred and refluxed gently for 4 h. Et₂ O (150 mL) was added after cooling and the organic layer was washed sequentially with water, saturated aqueous NaHCO₃, and brine. Drying over Na₂ SO₄ and concentration afforded 6.74 g of an orange foam. The crude product was purified by MPLC using 1:9 EtOAc:hexanes to give 1.90 g (23%) of the 2-(4-fluorophenyl) isomer and 1.15 g (14%) of the 1-(4-fluorophenyl) isomer, each as an orange solid. The 2-(4-fluorophenyl) isomer was recrystallized from EtOAc:Et₂ O to afford Compound 122 as a pale orange solid, m.p. 148°-150° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.6-2.0 (complex, 4), 2.72 (dd, 1, J=10.5, 13.5 Hz), 2.75-3.0 (complex), 3.15 (m, 1), 3.56 (dd, 1, J=4, 13.5 Hz), 7.2-7.7 (complex, 13), 9.87 (s, 1); IR (KBr) 1510, 1222 cm⁻¹ ; MS (DCI) m/z 411 (base). HRMS (EI) Cacld for C₂₇ H₂₃ FN₂ O: 410.179428. Found: 410.175457.

The 1-(4-fluorophenyl) isomer was recrystallized from EtOAc:hexanes to provide analytically pure Compound 123 as an orange solid, m.p. 155-156; ¹ H NMR (CDCl₃, 300 MHz) 1.7-1.9 (complex, 4), 2.46 (dd, 1, J=10.5, 13.5 Hz), 2.61 (dd, 1, J=4, 13.5 Hz), 2.73 (dt, 1, J=16.5, 8 Hz), 3.02 (dt, 1, J=16.5, 4 Hz), 3.30 (m, 1), 6.89 (d, 2, J=8 Hz), 7.2-7.6 (complex, 11), 10.08 (s, 1); IR (KBr) 1691, 1512 cm⁻¹ ; MS (DCI) m/z 411 (base). Anal. Calcd. for C₂₇ H₂₃ FN₂ O: C, 79.00; H, 5.65; N, 6.82. Found: C, 79.22; H, 5.54; N, 6.61.

General procedure for the preparation of 7-substituted 4,5,6,7-tetrahydroindazole-3-carboxaldehydes shown in Tables 3A and 3B (RS step g):

A solution of 10 mmol of the appropriately substituted diketone from Table 2 in 100 mL of absolute EtOH or MeOH was treated with 11.5 mmol of a base (NaOAc, Et₃ N, or pyridine) and 10.5 mmol of the appropriately substituted hydrazine hydrochloride. After stirring overnight under N₂, the solvent was removed by rotary evaporation and the residue was dissolved in 50 mL of THF. A 25 mL portion of 1N aqueous HCl was added and the mixture was stirred and refluxed gently for 4 h. After cooling, 100 mL of Et₂ O was added and the organic layer was washed sequentially with water, saturated aqueous NaHCO₃, and brine. Drying over Na₂ SO₄ and concentration afforded the crude product as a mixture of 2-aryl and 1-aryl isomers in ratios ranging from 1:1 to 1:3. The crude mixture was purified by recrystallization and/or MPLC; the 2-aryl isomer eluted before the 1-aryl isomer in all cases.

                  TABLE 3A                                                         ______________________________________                                          ##STR17##                                                                     Com-                                                                           pound                                Mass                                      Num-                                 Spectrum                                  ber   R.sub.1  R.sub.2        mp (°C.)                                                                       [M + H].sup.+                             ______________________________________                                         124   4-FPh    (1-Nap)CH.sub.2                                                                               183-184                                                                               385                                       125   4-FPh    (2-ClPh)CH.sub.2                                                                              137-138                                                                               369                                       126   4-FPh    (2-Et)Bu       121-122                                                                               329                                       127   4-FPh    (2-Nap)CH.sub.2                                                                               foam   385                                       128   4-FPh    (3-MeOPh)CH.sub.2                                                                             93-94  365                                       129   4-FPh    (3,4-di-       117-119                                                                               395                                                      MeOPh)CH.sub.2                                                  130   4-FPh    (4-ClPh)CH.sub.2                                                                              134-135                                                                               369                                       131   4-FPh    (4-FPh)CH.sub.2                                                                               128-131                                                                               353                                       132   4-FPh    (4-i-PrPh)CH.sub.2                                                                            112-113                                                                               377                                       133   4-FPh    (4-MePh)CH.sub.2                                                                              117-118                                                                               349                                       134   4-FPh    (4-MeOPh)CH.sub.2                                                                             104-107                                                                               365                                       135   4-FPh    (4-t-BuPh)CH.sub.2                                                                            139-140                                                                               391                                       136   4-FPh    c-Hex          119- 121                                                                              327                                       137   4-FPh    Et             95-97  273                                       138   4-FPh    Me             124-125                                                                               259                                       139   4-FPh    n-Pr           oil    287                                       140   4-FPh    Ph             71-73  321                                       141   4-FPh    PhCH.sub.2     144-145                                                                               335                                       142   4-FPh    Ph(CH.sub.2).sub.2                                                                            97-99  349                                       143   4-FPh    Ph(CH.sub.2).sub.3                                                                            oil    363                                       144   4-FPh    PhCHCHCH.sub.2 106-108                                                                               361                                       145   4-FPh    s-Bu           86-89  301                                       296   t-Bu     (1-Nap)CH.sub.2                                                                               119-120                                                                               347                                       ______________________________________                                    

                  TABLE 3B                                                         ______________________________________                                          ##STR18##                                                                     Com-                                                                           pound                                Mass                                      Num-                                 Spectrum                                  ber   R.sub.1  R.sub.2        mp (°C.)                                                                       [M + H].sup.+                             ______________________________________                                         146   4-FPh    (1-Nap)CH.sub.2                                                                               116-117                                                                               385                                       147   4-FPh    (2-ClPh)CH.sub.2                                                                              glass  369                                       297   4-FPh    (2-Et)Bu       foam   329                                       148   4-FPh    (2-Nap)CH.sub.2                                                                               122-123                                                                               385                                       149   4-FPh    (3-MeOPh)CH.sub.2                                                                             foam   365                                       150   4-FPh    (3,4-di-       109-110                                                                               395                                                      MeOPh)CH.sub.2                                                  151   4-FPh    (4-ClPh)CH.sub.2                                                                              126-128                                                                               369                                       152   4-FPh    (4-FPh)CH.sub.2                                                                               oil    353                                       153   4-FPh    (4-i-PrPh)CH.sub.2                                                                            oil    377                                       154   4-FPh    (4-MePh)CH.sub.2                                                                              foam   349                                       155   4-FPh    (4-MeOPh)CH.sub.2                                                                             oil    365                                       156   4-FPh    (4-t-BuPh)CH.sub.2                                                                            124-125                                                                               391                                       157   4-FPh    c-Hex          oil    327                                       158   4-FPh    Et             72-74  273                                       159   4-FPh    Me             79-80  259                                       160   4-FPh    n-Pr           50-53  287                                       161   4-FPh    Ph             139-140                                                                               321                                       162   4-FPh    PhCH.sub.2      99-100                                                                               335                                       163   4-FPh    Ph(CH.sub.2).sub.2                                                                            89-90  349                                       164   4-FPh    Ph(CH.sub.2).sub.3                                                                            100-102                                                                               363                                       165   4-FPh    PhCHCHCH.sub.2 104-105                                                                               361                                       166   4-FPh    s-Bu           oil    301                                       298   t-Bu     (1-Nap)CH.sub.2                                                                               142-143                                                                               347                                       ______________________________________                                    

EXAMPLE 4 3-Acetoxymethyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole (CP 167, RS step h)

Et₃ N (0.717 mL, 0.520 g, 5.14 mmol) was added to a stirring suspension of 1.00 g (5.04 mmol) of 2-acetoxyacetylcyclohexanone (Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982, 19, 117-121) and 0.820 g (5.04 mmol) of 4-fluorophenylhydrazine•HCl in 20 mL of absolute EtOH. The resulting solution was stirred under N₂ for 4 h at room temperature and refluxed for 6 h. The mixture was concentrated and the residue was partitioned between 100 mL of Et₂ O and 50 mL of dilute aqueous HCl. The Et₂ O layer was washed with water, saturated aqueous NaHCO₃, and brine. After drying over Na₂ SO₄, the solution was concentrated to give 1.43 g of light brown solid. Recrystallization from EtOAc:hexanes afforded 0.753 g (52%) of the title compound as a white solid, m.p. 128.5°-129.5° C.; ¹ H NMR (CDCl₃, 400 MHz) 1.85 (m, 4), 2.07 (s, 3), 2.60 (t, 2, J=6 Hz), 2.73 (t, 2, J=6 Hz), 5.00 (s, 2), 7.15 (t, 2, J=9 Hz), 7.45 (dd, 2, J=5, 9 Hz); IR (KBr) 1740, 1220 cm⁻¹ ; MS (DCI) m/z 289 (base), 228 . Anal. Calcd. for C₁₆ H₁₇ FN₂ O₂ : C, 66.65; H, 5.94; N, 9.72. Found: C, 66.74; H, 5.89; N, 9.61.

General procedure for the preparation of acetates shown in Table 4 (RS step h):

A mixture of 10 mmol of the appropriate 2-acetoxyacetylcycloalkanone (2-acetoxyacetylcyclopentanone, Dolmazon, R. J. Heterocyclic Chem., 1988, 25, 751-7; 2-acetoxyacetylcyclohexanone, Dolmazon, R.; Gelin, S. J. Heterocyclic Chem., 1982, 19, 117-21), 10.5 mmol of Et₃ N, and 10 mmol of appropriately substituted hydrazine in 40 mL of absolute EtOH was stirred under N₂ for 4-5 h and refluxed for 6-8 h. The solvent was evaporated and the resulting residue was partitioned between Et₂ O and 0.1N HCl. The Et₂ O layer was washed with water, saturated aqueous NaHCO₃, and brine. After drying over Na₂ SO₄, the solution was concentrated and the crude product was purified by recrystallization and/or MPLC. The 2-acetoxyacetylcyclopentanone reaction afforded a 9:1 mixture of 1-aryl:2-aryl isomers, while the 2-acetoxyacetylcyclohexanone reaction gave only the 2-aryl isomer.

                  TABLE 4                                                          ______________________________________                                          ##STR19##                                                                     Compound                           Mass Spectrum                               Number  n      R.sub.1    mp (°C.)                                                                         [M + H].sup.+                               ______________________________________                                         168     0      1-(4-FPh)  85-86    275                                         169     0      2-(4-FPh)  87-88    275                                         170     1      2-(4-ClPh) oil      305                                         ______________________________________                                    

EXAMPLE 5 2-(4-Fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-methanol (CP 171, RS step i)

Compound 167 (24.3 mmol, 7.00 g) was dissolved in 125 mL of MeOH and stirred while 26.7 mL of 1N aqueous NaOH was added. After 30 min the resulting cloudy suspension was concentrated and partitioned between 200 mL of EtOAc and 100 mL of water. The organic layer was washed with water and brine and was dried over Na₂ SO₄. The solution was concentrated to give 5.85 g of orange solid. Recrystallization from EtOAc gave 4.08 g (68%) of the title compound as off-white crystals, m.p. 163°-164° C.; ¹ H NMR (CDCl₃, 400 MHz) 1.80 (m, 4), 2.52 (t, 1, J=5 Hz), 2.86 (t, 2, J=6 Hz), 2.71 (t, 2, J=6 Hz), 4.52 (d, 2, J=5 Hz), 7.12 (2, t, J=9 Hz), 7.58 (dd, 2, J=5, 9 Hz); ¹³ C NMR (DMSO-d₆, 25 MHz) 19.8, 23.0 (triple), 52.1, 115.7 (d, J_(C-F) =23 Hz), 116.6, 125.2 (d, J_(C-F) =8 Hz), 136.5, 137.9, 148.8, 160.6 (d, J_(C-F) =244 Hz); IR (KBr) 3200 (broad), 1510 cm⁻¹ ; MS (DCI) m/z 247 (base). Anal. Calcd. for C₁₄ H₁₅ FN₂ O: C, 68.28; H, 6.14; N, 11.37. Found: C, 68.47; H, 6.02; N, 11.35.

General procedure for the preparation of alcohols shown in Table 5 (RS step i):

The appropriate acetate from Table 4 (10 mmol) was dissolved in 50 mL of MeOH and stirred while 11 mmol of 1N aqueous NaOH was added. The resulting suspension was stirred 0.5-24 h and worked up by one of two methods. In the first method, the mixture was concentrated and partitioned between water and solvent. The organic phase was washed with water and brine, dried over Na₂ SO₄, and concentrated. Alternatively, the reaction mixture was filtered to remove the solids and the filtrate was treated with water to precipitate the remaining product. The combined solids were dissolved in CHCl₃, washed with brine, and concentrated. The crude product was purified by recrystallization or a combination of recrystallization and MPLC.

                  TABLE 5                                                          ______________________________________                                          ##STR20##                                                                     Compound                           Mass Spectrum                               Number  n      R.sub.1    mp (°C.)                                                                         [M + H].sup.+                               ______________________________________                                         172     0      1-(4-FPh)  85-86    233                                         173     0      2-(4-FPh)  170-171  233                                         174     1      2-(4-ClPh) 184.5-185                                                                               263                                         ______________________________________                                    

EXAMPLE 6 2-(4-Fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 175, RS step e, followed by RS step k)

A solution of 2.80 g (25 mmol) of cycloheptanone and 4.71 g (25 mmol) of ethyl (tetrahydropyranyloxy)acetate (Ireland, R. E.; Wipf, P. Tetrahedron Lett., 1989, 30, 919-22) in 20 mL of Et₂ O was added over the course of 1 h to an ice-cold, stirring mixture of hexane-washed NaH and 0.12 mL (2 mmol, 0.092 g) of absolute EtOH in 10 mL of Et₂ O under N₂. The light brown mixture was allowed to warm to room temperature and was stirred overnight. MeOH (5 mL) was added and the solution was poured onto 200 mL of saturated aqueous NH₄ Cl. After acidification to pH 2 with 1N aqueous HCl, the mixture was extracted with Et₂ O. The organic layer was washed with brine, dried over Na₂ SO₄, and concentrated to give 5.61 g of crude 2-[(tetrahydropyranyloxy)acetyl]cycloheptanone as a light brown oil.

The crude diketone was dissolved in 60 mL of absolute EtOH and combined with 3.07 mL (22 mmol, 2.23 g) of Et₃ N and 3.45 g (21.1 mmol) of 4-fluorophenylhydrazine•HCl. The resulting solution was stirred under N₂ overnight and refluxed for 4 h. A 30 mL portion of 1N aqueous HCl was added and the mixture was refluxed for an additional hour. The mixture was cooled and extracted with 200 mL of Et₂ O. The organic phase was washed with water, saturated aqueous NaHCO₃, and brine and dried over Na₂ SO₄. The solution was concentrated to give 5.50 g of a 1.2:1 mixture of 1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol and the title compound as a brown oil. The crude product was crystallized from EtOAc:Et₂ O to afford 0.97 g (18%) of the title compound as an off-white solid, m.p. 177°-178° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.72 (m, 4), 1.85 (m, 2), 2.60 (m, 2), 2.80 (m, 2), 4.51 (d, 2, J=5 Hz), 7.15 (m, 2), 7.60 (m, 2); IR (KBr) 3240 (broad), 1513, 1223 cm⁻¹ ; MS (DCI) m/z 261 (base). Anal. Calcd. for C₁₅ H₁₇ FN₂): C, 69.21; H, 6.58; N, 10.76. Found: C, 69.15; H, 6.77; N, 10.63.

EXAMPLE 7 Ethyl 2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 176, RS step f, followed by RS step 1)

Hydrazine hydrate (30.3 mmol, 1.52 g, 1.47 mL) was added dropwise under N₂ to a stirring solution of ethyl α,2-dioxocycloheptaneacetate (Tsuboi, S.; Nishiyama, E.; Furutani, H.; Utaka, M.; Takeda, A. J. Org. Chem., 1987, 52, 1359-62) in 60 mL of MeOH. The reaction mixture, which had become warm during the addition, was allowed to cool to room temperature and was stirred overnight. The solvent was evaporated and the resulting oil was dissolved in CH₂ Cl₂ and washed with water and brine. After drying over Na₂ SO₄, the solution was concentrated to give 6.36 g of pale yellow solid. Recrystallization from EtOAc:hexanes afforded 3.44 g (52%) of the title compound as a white solid, m.p. 90°-92° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.38 (t, 3, J=7 Hz), 1.67 (m, 4), 1.84 (m, 2), 2.80 (m, 2), 2.93 (m, 2 ), 4.37 (q, 2, J=7 Hz), 7.0 (broad s, 1); IR (KBr) 1719 cm⁻¹ ; MS (DCI) m/z 209 (base). Anal. Calcd. for C₁₁ H₁₆ N₂ O₂ : C, 63.44; H, 7.74; N, 13.45. Found: C, 63.48; H, 7.76; N, 13.64.

EXAMPLE 8 Ethyl 2-(4-fluorobenzyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 177, RS step m) and ethyl 1-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-carboxylate (CP 178, RS step m)

A solution of 7.90 g (37.9 mmol) of Compound 176 in 35 mL of DMF was added dropwise under N₂ to a suspension of hexane-washed NaH (41.7 mol, 1.67 g of a 60% oil suspension) in 20 mL of DMF. When the addition was complete, the mixture was heated at 140° C. with an oil bath for 15 min. A solution of 5.00 mL (41.7 mmol, 6.03 g) of 4-fluorobenzyl chloride in 5 mL of DMF was added and the mixture was heated for an additional 30 min. After cooling, 400 mL of Et₂ O was added and the solution was poured onto 250 mL of saturated aqueous NH₄ Cl. The aqueous layer was extracted with two 50 mL portions of Et₂ O and the combined organic phases were washed with three 100 mL portions of water and once with brine. The organic solution was dried over Na₂ SO₄ and concentrated to give 11.9 g of a 1:1 mixture of the title compounds as a yellow oil. Purification by MPLC afforded, in the earlier fractions, 3.85 g (32%) of pure 2-(4-fluorobenzyl) isomer as a colorless oil; ¹ H NMR (CDCl₃, 100 MHz) 1.31 (t, 3, J=7 Hz), 1.70 (m, 6), 2.83 (m, 4), 4.29 (q, 2, J=7 Hz), 5.58 (s, 2), 6.9-7.4 (complex, 4). The later-eluting fractions contained 4.94 g (42%) of the 1-(4-fluorobenzyl) isomer as a colorless oil; ¹ H NMR (CDCl₃, 100 MHz) 1.40 (t, 3, J=7 Hz), 1.4-2.0 (complex, 6), 2.55 (m, 2), 2.95 (m, 2), 4.41 (q, 2, J=7 Hz), 5.35 (s, 2), 7.00 (m, 4).

EXAMPLE 9 2-(4-Fluorobenzyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 179, RS step n)

A solution of 1.43 g (4.52 mmol) of Compound 177 in 13 mL of THF under N₂ was added dropwise over a 10 min period to an ice cold suspension of 0.113 g (2.83 mmol) of LiAlH₄ in 7 mL of THF. After 30 min in the cold, the suspension was allowed to warm to room temperature and was stirred for 2 h. Et₂ O (50 mL) was added, followed sequentially by 0.12 mL of water, 0.12 mL of 15% aqueous NaOH, and 0.36 mL of water, dropwise over a 1 h period. The white suspension was stirred overnight, treated with MgSO₄, and stirred 30 min more. The solids were removed by filtration and were washed with CH₂ Cl₂. The combined filtrates were concentrated to afford 1.24 g of a white solid, which was recrystallized to give 0.998 g (80%) of the title compound as white needles, m.p. 156°-157° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.55-1.70 (complex, 7), 1.82 (m, 2), 2.47 (m, 2), 2.74 (m, 2), 4.48 (d, 2, J=6 Hz), 5.27 (s, 2), 6.98 (t, 2, J=7 Hz), 7.12 (m, 2); IR (KBr) 3170 (broad), 1517, 1231, 1016 cm⁻¹ ; MS (DCI) m/z 275 (base), 257. Anal. Calcd. for C₁₆ H₁₉ FN₂ O: C, 70.05; H, 6.98; N, 10.21. Found: C, 69.98; H, 6.98; N, 10.28.

EXAMPLE 10 1-(4-Fluorobenzyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 180, RS step n)

Following the procedure described above, 4.82 mmol (15.23 g) of Compound 178 gave 4.12 g (98%) of the title compound as an amber oil, which was used without purification; ¹ H NMR (CDCl₃, 100 MHz) 1.70 (m, 6), 2.57 (m, 4), 3.0 (broad s, 1), 4.59 (d, 2, J=6 Hz), 5.20 (s, 2), 7.00 (m, 4).

EXAMPLE 11 2-(4-Fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole-3-carboxaldehyde (CP 181, RS step j)

Pyridinium chlorochromate (22.0 mmol, 4.74 g) was suspended in 50 ml of CH₂ Cl₂. Compound 171 (14.8 mmol, 3.64 g) was added in small portions over a 5 min period and the resulting suspension was stirred at room temperature for 4 h. A 300 mL portion of Et₂ O was added and the mixture was filtered through a pad of Florisil. The tarry residue remaining in the flask was sonicated twice with 100 mL of Et₂ O and the organic solutions were also filtered through Florisil. The Florisil pad was washed thoroughly with Et₂ O and the combined organic solutions were dried over Na₂ SO₄ and concentrated to give 3.57 g of an off-white solid. The crude product was recrystallized from Et₂ O:hexanes to give 1.71 g (42%) of white crystals, m.p. 80°-81° C. (the mother liquors were concentrated to give 1.67 g (47%) of a white solid which was judged to be pure enough to carry on); ¹ H NMR (CDCl₃, 400 MHz) 1.85 (m, 4), 2.77 (t, 2, J=6 Hz), 2.88 (t, 2, J=6 Hz), 7.20 (m, 2), 7.45 (m, 2), 9.86 (s, 1); IR (KBr) 1670, 1575 cm⁻¹ ; MS (DCI) m/z 245 (base). Anal. Calcd. for C₁₄ H₁₃ FN₂ O: C, 68.84; H, 5.36; N, 11.47. Found: C, 68.79; H, 5.40; N, 11.39.

General procedure for the preparation of aldehydes shown in Table 6 (RS step j):

Method A: MnO₂ (100-120 mmol) was added in one portion to a stirring suspension of 10 mmol of the alcohol from Example 10 in 60 mL of benzene. The mixture was refluxed gently under N₂ until TLC analysis indicated that the starting material was completely consumed. After cooling, the slurry was filtered through a Celite pad and the black solids were washed with 250 mL of CH₂ Cl₂. The filtrate was concentrated and the crude product was purified by MPLC or recrystallization.

Method B: To a stirring suspension of pyridinium chlorochromate (10 mmol) in 25 mL of CH₂ Cl₂ was added, in approximately five portions, the appropriately substituted alcohol from Table 5 or Examples 5, 6, or 9, as a solid. The resulting suspension was stirred for 2-4 h at room temperature. Et₂ O (150 mL) was added and the mixture was sonicated for 5-10 min. The supernatant was decanted through a pad of Florisil and the remaining solids were sonicated twice with 50 mL portions of Et₂ O, which in turn were filtered. The Florisil pad was washed thoroughly with Et₂ O and the combined filtrates were concentrated to give the crude product, which was purified by recrystallization.

                  TABLE 6                                                          ______________________________________                                          ##STR21##                                                                     Com-                                   Mass                                    pound                                  spectrum                                Num-  Meth-                            m/z                                     ber   od      n     R.sub.1     mp (°C.)                                                                       [M + H].sup.+                           ______________________________________                                         182   B       0     1-(4-FPh)   122-123                                                                               231                                     183   B       0     2-(4-FPh)   79-80  231                                     184   B       1     2-(4-ClPh)  93-94  261                                     185   B       2     2-(4-FPh)   oil    259                                     186   A       2     1-(4-FPhCH.sub.2)                                                                          oil    273                                     187   B       2     2-(4-FPhCH.sub.2)                                                                          oil    273                                     ______________________________________                                    

EXAMPLE 12 Methyl (E)-7-[7-[(1,1'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3-hydroxy-5-oxo-6-heptenoate (CP 188, RS step t)

Compound 122 (2.68 mmol, 1.10 g), LiCl (3.08 mmol, 0.131 g), and 1.18 g (3.08 mmol) of methyl 3-[(t-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate (Theisen, P. D.; Heathcock, C. H. J. Org. Chem., 1988, 53, 2374-81) were combined in 15 mL of CH₃ CN. DBU (2.95 mmol, 0.449 g, 0.441 mL) was added and the resulting clear, orange solution was stirred under N₂ for 6 h. The mixture was diluted with 100 mL of Et₂ O and washed successively with 50 mL of 5% aqueous NaHSO₄, water, and brine. After drying over Na₂ SO₄, the solution was concentrated to give 2.00 g of orange oil. The crude mixture was dissolved in 25 mL of CH₃ CN, treated with 2.5 mL of 48% aqueous HF, and stirred for 5 h. Et₂ O (100 mL) was added and the acid was quenched by careful addition of saturated aqueous NaHCO₃. The ethereal solution was washed with brine, dried over Na₂ SO₄, and concentrated to give 1.54 g of orange foam. The crude product was purified by MPLC using 1:2 EtOAc:hexanes to afford 0.22 g (15%) of the title compound as a yellow solid and an additional 0.50 g (34%) as a pale yellow solid which crystallized directly from the chromatography fractions, m.p. 137°-138° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.4-2.1 (complex, 4), 2.56 (d, 2, J=6 Hz), 2.71 (m, 3), 2.80 (d, 2, J=6 Hz), 3.15 (m, 1), 3.47 (d, 1, J=4 Hz), 3.56 (dd, 1, J=4, 13.5 Hz), 3.71 (s, 3), 4.52 (m, 1), 6.51 (d, 1, J=16 Hz), 7.1-7.7 (complex, 14); IR (KBr) 3450 (broad), 1734, 1603, 1512 cm⁻¹ ; MS (DCI) m/z 553, 451 (base). Anal. Calcd. for C₃₄ H₃₃ FN₂ O₄ : C, 73.89; H, 6.02; N, 5.07. Found: C, 73.94; H, 6.01; N, 5.03.

General procedure for the preparation of 7-substituted (E)-3-hydroxy-5-oxo-6-heptenoates shown in Table 7 (RS step t):

The appropriately substituted aldehyde (10 mmol) from Table 3A or 3B was combined with 11.5 mmol of LiCl and 11.5 mmol of methyl 3-[(t-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate in 25 mL of CH₃ CN. DBU (11 mmol) was added and the resulting clear solution was stirred for 4-6 h, becoming slightly cloudy during that time. The mixture was diluted with 100 mL of Et₂ O and washed successively with 100 mL of 5% aqueous NaHSO₄, water, and brine. After drying over Na₂ SO₄, the solution was concentrated to give the crude silyloxy keto ester. The crude residue was dissolved in 100 mL of CH₃ CN and was treated with 10 mL of 48% aqueous HF. After TLC analysis indicated complete consumption of silyloxy keto ester, 200 mL of Et₂ O was added and the HF was quenched by careful addition of saturated aqueous NaHCO₃. The ethereal solution was washed with brine, dried over Na₂ SO₄, and concentrated to give the crude product, which was purified by MPLC.

                  TABLE 7                                                          ______________________________________                                          ##STR22##                                                                     Com-                                 Mass                                      pound                                Spectrum                                  Num-                            mp   m/z                                       ber   R.sub.1    R.sub.2        (°C.)                                                                        [M + H].sup.+                             ______________________________________                                         189   1-(4-FPh)  Ph(CH.sub.2).sub.2                                                                            oil  491                                       190   2-(4-FPh)  (1-Nap)CH.sub.2                                                                               foam 527                                       191   2-(4-FPh)  (2-Nap)CH.sub.2                                                                               foam 527                                       192   2-(4-FPh)  (4-i-PrPh)CH.sub.2                                                                            oil  519                                       193   2-(4-FPh)  (4-t-BuPh)CH.sub.2                                                                            foam 533                                       194   2-(4-FPh)  Ph             foam 463                                       195   2-(4-FPh)  PhCHCHCH.sub.2 oil  503                                       ______________________________________                                    

EXAMPLE 13 Methyl (E)-(3RS,5SR)-7-[7-[(1,1'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoate (CP 39, RS step u)

Compound 188 (1.21 mmol, 0.67 g) was dissolved in 1.5 mL of MeOH and 5 mL of THF and treated, dropwise, with 1.33 mL (1.33 mmol) of a 1.0M solution of Et₃ B in THF. Air (5 mL) was bubbled into the solution via syringe and the resulting solution was stirred under N₂ for 2 h and then cooled to -78° C. After addition of solid NaBH₄ in one portion, the mixture was allowed to warm slowly to room temperature and was stirred overnight. Et₂ O (100 mL) and saturated aqueous NH₄ Cl (50 mL) were added. The ethereal solution was washed with brine, dried over Na₂ SO₄, and concentrated to give a yellow oil. The oil was dissolved in MeOH, stirred under air overnight, and concentrated to provide 0.74 g of pale yellow foam. Purification by MPLC using 45:55 EtOAc:hexanes afforded a white foam which crystallized upon addition of Et₂ O, giving 281 mg (42%) of the title compound as a white solid, m.p. 118°-119° C. (the mother liquors gave 77 mg (12%) of additional product as a white foam); ¹ H NMR (CDCl₃, 300 MHz) 1.4-2.0 (complex, 6), 2.49 (d, 2, J=6 Hz), 2.6-2.8 (complex, 3), 3.10 (m, 1), 3.56 (dt, 1, J=13.5, 3.5 Hz), 3.62 (s, 1), 3.71 (s, 3), 3.78 (s, 1), 4.28 (m, 1), 4.48 (m, 1), 6.01 (dd, 1, J=6, 16 Hz), 6.45 (d, 1, J=16 Hz); ¹³ C NMR (CDCl₃, 75 MHz) 21.6, 22.8, 27.9, 36.2, 40.3, 41.3, 42.7, 51.9, 68.3, 72.5, 115.7, 116.0 (J_(C-F) =23 Hz), 118.0, 127.0, 127.3 (J_(C-F) =38 Hz), 128.7, 129.8, 135.0, 135.3, 136.1, 138.8, 139.8, 141.1, 153.3, 161.7 (J_(C-F) =247 Hz), 172.9; IR (KBr) 3400 (broad), 1734, 1513 cm⁻¹ ; MS (DCI) m/z 555 (base), 537, 523. Anal. Calcd. for C₃₄ H₃₅ FN₂ O₄ : C, 73.63; H, 6.36; N, 5.05. Found: C, 73.33; H, 6.60; N, 5.06.

General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoates shown in Table 8 (RS step u):

The appropriately substituted hydroxy keto ester from Table 7 (10 mmol), dissolved in 10 mL of MeOH and 30 mL of THF, was treated with 11 mmol of a 1.0M THF solution of Et₃ B. Air (about 20 mL) was bubbled into the solution via syringe and the resulting solution was stirred under N₂ for 2 h. After cooling to -78° C., the solution was treated with 11 mmol of solid NaBH₄ in one portion, causing some gas evolution. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH₄ Cl was added and the mixture was extracted with Et₂ O. The organic extracts were washed with brine, dried over Na₂ SO₄, and concentrated to dryness. The residue, which smelled of excess Et₃ B, was then dissolved in MeOH and stirred vigorously under air until TLC analysis showed complete conversion of the boron intermediates to the desired product (4-24 h). The MeOH was removed by rotary evaporation and the crude material was purified by MPLC.

                                      TABLE 8                                      __________________________________________________________________________      ##STR23##                                                                     Compound                         Mass Spectrum                                 Number R.sup.1 R.sub.2     mp (°C.)                                                                      m/z [M + H].sup.+                             __________________________________________________________________________     40     1-(4-FPh)                                                                              Ph(CH.sub.2).sub.2                                                                         foam  493                                           41     2-(4-FPh)                                                                              (1-Nap)CH.sub.2                                                                            foam  529                                           42     2-(4-FPh)                                                                              (2-Nap)CH.sub.2                                                                            foam  529                                           43     2-(4-FPh)                                                                              (4-i-PrPh)CH.sub.2                                                                         foam  521                                           44     2-(4-FPh)                                                                              (4-t-BuPh)CH.sub.2                                                                         foam  535                                           45     2-(4-FPh)                                                                              Ph          foam  465                                           46     2-(4-FPh)                                                                              PhCHCHCH.sub.2                                                                             oil   505                                           __________________________________________________________________________

EXAMPLE 14 (E)-(3RS,5SR)-7-[7-[(1,1'-Biphenyl-4-yl)methyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoic acid•Sodium salt•Dihydrate (CP 1, RS step v)

Aqueous NaOH (0.25 N, 0.392 mmol, 1.57 mL) was added slowly to an ice-cold solution of Compound 39 (0.400 mmol, 222 mg) in 10 mL of MeOH. When the addition was complete, the solution was allowed to warm to room temperature and stirred for 2 h. The solution was concentrated to dryness using a rotary evaporator and the residue was dissolved in 40 mL of water. The slightly cloudy solution was suction filtered through a coarse frit, frozen in a -78° C. bath, and lyophilized. The product was dried in a vacuum oven over Drierite to provide 219 mg (93%) of the title compound as a fluffy, white solid; ¹ H NMR (DMSO-d₆, 400 MHz) 1.3-2.0 (complex, 7), 2.05 (dd, 1, J=4, 15 Hz), 2.4-2.7 (complex, 4), 3.01 (m, 1), 3.40 (m, 1), 3.75 (m, 1), 4.26 (m, 1), 5.13 (broad s, 1), 6.07 (dd, 1, J=5, 16 Hz), 6.36 (d, 1, J=16 Hz), 7.2-7.7 (complex, 13); IR (KBr) 3400 (broad), 1577, 1513 cm⁻¹ ; MS (FAB+) m/z 535, 563, 541, 167, 115 (base). Anal. Calcd. for C₃₃ H₃₂ FN₂ NaO₄ •2 H₂ O: C, 66.21; H, 6.06; N, 4.68. Found: C, 66.39; H, 5.67; N, 4.62.

General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoic acid sodium salts shown in Tables 9A and 9B (RS step v)

Aqueous NaOH (0.25 N, 0.98 mmol) was added slowly to an ice-cold methanolic solution (15 mL) of 1.0 mmol of the appropriately substituted dihydroxy ester of Table 8, 13A, or 13B or Example 20. When the addition was complete, the solution was allowed to warm to room temperature and stir for 2 h until TLC analysis indicated that nearly all starting material had been consumed. The solution was concentrated to dryness using a rotary evaporator and the residue was dissolved in 40 mL of water. The slightly cloudy solution was suction filtered through a coarse frit, frozen in a -78° C. bath, and lyophilized. The product was dried in a vacuum oven over Drierite to provide the desired sodium salt as a white, fluffy powder.

                                      TABLE 9A                                     __________________________________________________________________________      ##STR24##                                                                     Compound                       Mass Spectrum                                   Number n  R.sub.1  R.sub.2     m/z [M + H].sup.+                               __________________________________________________________________________     2      0  4-FPh    H           383                                             3      1  4-FPh    (4-FPh)CH.sub.2                                                                            505                                             4      1  4-FPh    c-Hex       497                                             5      1  4-FPh    Et          425                                             6      1  4-FPh    Me          411                                             7      1  4-FPh    Ph(CH.sub.2).sub.2                                                                         501                                             8      1  4-FPh    PhCHCHCH.sub.2                                                                             513                                             9      2  4-FPhCH.sub.2                                                                           H           425                                             __________________________________________________________________________

                                      TABLE 9B                                     __________________________________________________________________________      ##STR25##                                                                     Compound                              Mass Spectrum                            Number                                                                               n R.sub.1 R.sub.2      R.sub.3                                                                           Y     m/z [M + H].sup.+                        __________________________________________________________________________     10    0 4-FPh   H            H  CHCH  383                                      11    1 4-FPh   (1-Nap)CH.sub.2                                                                             H  CHCH  537                                      12    1 4-FPh   (2-ClPh)CH.sub.2                                                                            H  CHCH  521                                      13    1 4-FPh   (2-Nap)CH.sub.2                                                                             H  CHCH  537                                      14    1 4-FPh   (3-MeOPh)CH.sub.2                                                                           H  CHCH  517                                      15    1 4-FPh   (3,4-di-MeOPh)CH.sub.2                                                                      H  CHCH  547                                      16    1 4-FPh   (4-ClPh)CH.sub.2                                                                            H  CHCH  520                                      17    1 4-FPh   (4-FPh)CH.sub.2                                                                             H  CHCH  505                                      18    1 4-F Ph  (4-i-PrPh)CH.sub.2                                                                          H  CHCH  529                                      19    1 4-FPh   (4-MePh)CH.sub.2                                                                            H  CHCH  501                                      20    1 4-FPh   (4-MeOPh)CH.sub.2                                                                           H  CHCH  517                                      21    1 4-FPh   (4-t-BuPh)CH.sub.2                                                                          H  CHCH  543                                      22    1 4-FPh                                                                  6,7-Benzo-                      CHCH  445                                      23    1 4-FPh   c-Hex        H  CHCH  479                                      24    1 4-FPh   Et           H  CHCH  425                                      25    1 4-FPh   H            H  CHCH  397                                      26    1 4-ClPh  H            H  CHCH  413                                      27    1 4-FPh   H            H  CHCMe 411                                      28    1 4-FPh   Me           H  CHCH  411                                      29    1 4-FPh   n-Pr         H  CHCH  439                                      30    1 4-FPh   Ph           H  CHCH  473                                      31    1 4-FPh   PhCH.sub.2   H  CHCH  487                                      32    1 4-FPh   Ph(CH.sub.2).sub.2                                                                          H  CHCH  501                                      33    1 4-FPh   Ph(CH.sub.2).sub.3                                                                          H  CHCH  515                                      34    1 4-FPh   PhCHCHCH.sub.2                                                                              H  CHCH  513                                      35    1 4-FPh   s-Bu         H  CHCH  453                                      36     2                                                                               4-FPh                                                                  7,8-Benzo-                      CHCH  459                                      37    2 4-FPh   H            H  CHCH  411                                      38    2 4-FPhCH.sub.2                                                                          H            H  CHCH  425                                      __________________________________________________________________________

EXAMPLE 15 Ethyl (E)-3-[2-(4-fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-propenoate (CP 196, RS step o)

Triethylphosphonoacetate (3.03 mmol, 0.706 g, 0.625 mL) in 2.5 mL of THF was added slowly under N₂ to a stirring suspension of oil-free NaH (3.09 mmol, 0.074 g) in 5 mL of THF. After 45 min, the solution was cooled in an ice bath and Compound 162 (2.75 mmol, 0.92 g) in 10 mL of THF was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous NH₄ Cl (50 mL) was added and the mixture was extracted with 100 mL of Et₂ O. The organic phase was washed with brine, dried over Na₂ SO₄, and concentrated to give 1.29 g of amber oil. The crude product was crystallized from Et₂ O: hexanes to give 0.598 g (54%) of the title compound as an off-white solid, m.p. 117°-118° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.30 (t, 3, J=7 Hz), 1.4-2.1 (complex, 4), 1.6-1.8 (complex, 3), 3.10 (m, 1), 3.54 (dd, 1, J=4, 13.5 Hz), 4.22 (q, 2, J=7 Hz), 6.20 (d, 1, J=16 Hz), 7.1-7.4 (complex, 9), 7.48 (d, 1, J=16 Hz); IR (KBr) 1705 cm⁻¹ ; MS (DCI) m/z 405 (base). Anal. Calcd. for C₂₅ H₂₅ FN₂ O₂ : C, 74.24; H, 6.23; N, 6.93. Found: C, 74.31; H, 6.09; N, 6.91.

General procedure for the preparation of 3-substituted 2-propenoates shown in Tables 10A and 10B (RS step o):

A solution of 11 mmol of triethylphosphonoacetate or triethyl phosphonopropionate in 10 mL of THF was added slowly under N₂ to a stirring suspension of 11.5 mmol of NaH in 15 mL of THF. After 45 min, the solution was cooled in an ice bath and the appropriately substituted aldehyde (10 mmol) from Table 3A, 3B, or 6 in THF (25 mL) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous NH₄ Cl (100 mL) was added and the mixture was extracted with Et₂ O. The organic phase was washed with brine, dried over Na₂ SO₄, and concentrated. The crude product was crystallized or was carried on without purification.

                                      TABLE 10A                                    __________________________________________________________________________      ##STR26##                                                                     Compound                         Mass Spectrum                                 Number                                                                               n R.sub.1  R.sub.2    mp (°C.)                                                                     m/z [M + H].sup.+                             __________________________________________________________________________     197   0 4-FPh    H          113-114                                                                             301                                           198   1 4-FPh    (4-FPh)CH.sub.2                                                                           foam 411                                           199   1 4-FPh    c-Hex      oil  397                                           200   1 4-FPh    Et          99-100                                                                             343                                           201   1 4-FPh    Me         oil  329                                           202   1 4-FPh    PhCHCHCH.sub.2                                                                            foam 431                                           203   2 (4-FPh)CH.sub.2                                                                         H          75-76                                                                               343                                           __________________________________________________________________________

                                      TABLE 10B                                    __________________________________________________________________________      ##STR27##                                                                     Compound                                 Mass Spectrum                         Number                                                                               n R.sub.1 R.sub.2      Y      mp (°C.)                                                                     m/z [M + H].sup.+                     __________________________________________________________________________     204   0 4-FPh   H            CHCH   94-95                                                                               301                                   205   1 4-FPh   (2-ClPh)CH.sub.2                                                                            CHCH   oil  439                                   206   1 4-FPh   (2-Et)Bu     CHCH   oil  399                                   207   1 4-FPh   (2-Nap)CH.sub.2                                                                             CHCH   154-155                                                                             455                                   208   1 4-FPh   (3-MeOPh)CH.sub.2                                                                           CHCH   135-137                                                                             435                                   209   1 4-FPh   (3,4-di-MeOPh)CH.sub.2                                                                      CHCH   foam 465                                   210   1 4-FPh   (4-ClPh)CH.sub.2                                                                            CHCH   oil  439                                   211   1 4-FPh   (4-FPh)CH.sub.2                                                                             CHCH   oil  411                                   212   1 4-FPh   (4-MePh)CH.sub.2                                                                            CHCH   135-136                                                                             419                                   213   1 4-FPh   (4-MeOPh)CH.sub.2                                                                           CHCH   oil  435                                   214   1 4-FPh   (4-t-BuPh)CH.sub.2                                                                          CHCH   oil  461                                   215   1 4-FPh   c-Hex        CHCH   oil  419                                   216   1 4-FPh   Et           CHCH   oil  343                                   217   1 4-ClPh  H            CHCH   oil  331                                   218   1 4-FPh   H            CHCH     76-77.5                                                                           315                                   219   1 4-FPh   H            CHC(Me)                                                                               134-135                                                                             329                                   220   1 4-FPh   Me           CHCH   oil  329                                   221   1 4-FPh   n-Pr         CHCH   oil  357                                   222   1 4-FPh   Ph(CH.sub.2).sub.2                                                                          CHCH   oil  419                                   223   1 4-FPh   Ph(CH.sub.2).sub.3                                                                          CHCH   oil  433                                   224   1 4-FPh   PhCHCHCH.sub.2                                                                              CHCH   oil  431                                   225   1 4-FPh   s-Bu         CHCH   oil  371                                   226   2 4-FPh   H            CHCH   53-55                                                                               329                                   227   2 4-FPhCH.sub.2                                                                          H            CHCH   oil  343                                   __________________________________________________________________________

EXAMPLE 16 (E)-3-[2-(4-Fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-yl]2-propen-1-ol (CP 228, RS step p):

A 1.5M solution of (i-Bu)₂ AlH in toluene (6.53 mmol, 4.35 mL) was added under N₂ to an ice cold solution of 1.10 g (6.53 mmol) of Compound 196 in 11 mL of THF. The solution was stirred for 1.5 h and was quenched with 0.5 mL of MeOH. When the initial bubbling had ceased, 35 mL of 1N aqueous HCl was added and the mixture was extracted with 150 mL of ether. The organic phase was washed sequentially with water, saturated aqueous NaHCO₃, and brine. After drying over Na₂ SO₄, the solvent was evaporated to give 0.89 g of an off-white solid. Recrystallization from EtOAc:hexanes afforded 0.62 g (63%) of the title compound as a white solid, m.p. 185°-186° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.4-2.0 (complex, 5), 2.62 (m, 3), 3.05 (m, 1), 3.54 (dd, 1, J=4, 13.5 Hz), 4.27 (t, 2, J=5 Hz), 6.16 (dt, 1, J=16, 5.5 Hz), 6.43 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); IR (KBr) 3300, 1515 cm⁻¹ ; MS (DCI) m/z 363 (base), 345. Anal. Calcd. for C₂₃ H₂₃ FN₂ O: C, 76.22; H, 6.40; N, 7.73. Found: C, 75.73; H, 6.01; N, 7.91.

General procedure for the preparation of 3-substituted 2-propen-1-ols shown in Tables 11A and 11B (RS step p):

A 1.5M solution of (i-Bu)₂ AlH in toluene (24 mmol) was added under N₂ to an ice cold solution of 10 mmol of the appropriately substituted ester from Table 10A or 10B in 50 mL of THF. The solution was stirred for 1.5 h and was quenched with 2 mL of MeOH. When the initial bubbling had ceased, 100 mL of 1N aqueous HCl was added and the mixture was extracted with 300 mL of ether. The organic phase was washed sequentially with water, saturated aqueous NaHCO₃, and brine. After drying over Na₂ SO₄, the solvent was evaporated and the crude product was purified by recrystallization or MPLC.

                                      TABLE 11A                                    __________________________________________________________________________      ##STR28##                                                                     Compound                           Mass Spectrum                               Number                                                                               n R.sub.1  R.sub.2    mp (°C.)                                                                       m/z [M + H].sup.+                           __________________________________________________________________________     229   0 4-FPh    H          135-136                                                                               259                                         230   1 4-FPh    (4-FPh)CH.sub.2                                                                           171-173                                                                               381                                         231   1 4-FPh    c-Hex      oil    355                                         232   1 4-FPh    Et         yellow foam                                                                           301                                         233   1 4-FPh    Me         115-116                                                                               287                                         234   1 4-FPh    PhCHCHCH.sub.2                                                                            oil    389                                         235   2 (4-FPh)CH.sub.2                                                                         H          oil    301                                         __________________________________________________________________________

                                      TABLE 11B                                    __________________________________________________________________________      ##STR29##                                                                     Compound                                 Mass Spectrum                         Number                                                                               n R.sub.1  R.sub.2      Y     mp (°C.)                                                                     m/z [M + H].sup.+                     __________________________________________________________________________     236   0 4-FPh    H            CHCH  144-145                                                                             259                                   237   1 4-FPh    (2-ClPh)CH.sub.2                                                                            CHCH  177-178                                                                             397                                   238   1 4-FPh    (2-Et)Bu     CHCH  oil  357                                   239   1 4-FPh    (2-Nap)CH.sub.2                                                                             CHCH  205-207                                                                             413                                   240   1 4-FPh    (3-MeOPh)CH.sub.2                                                                           CHCH  foam 393                                   241   1 4-FPh    (3,4-di-MeOPh)CH.sub.2                                                                      CHCH  183-184                                                                             423                                   242   1 4-FPh    (4-ClPh)CH.sub.2                                                                            CHCH  204-206                                                                             397                                   243   1 4-FPh    (4-FPh)CH.sub.2                                                                             CHCH  183-185                                                                             381                                   244   1 4-FPh    (4-MePh)CH.sub.2                                                                            CHCH  184-186                                                                             377                                   245   1 4-FPh    (4-MeOPh)CH.sub.2                                                                           CH CH 172-173                                                                             393                                   246   1 4-FPh    (4-t-BuPh)CH.sub.2                                                                          CHCH  141-142                                                                             419                                   247   1 4-FPh    c-Hex        CHCH  oil  355                                   248   1 4-FPh    Et           CHCH  140-142                                                                             301                                   249   1 4-ClPh   H            CHCH  171-173                                                                             289                                   250   1 4-FPh    H            CHCH  145-146                                                                             273                                   251   1 4-FPh    H            CHC(Me)                                                                              149-150                                                                             287                                   252   1 4-FPh    Me           CHCH  139-140                                                                             287                                   253   1 4-FPh    n-Pr         CHCH  140-141                                                                             315                                   254   1 4-FPh    Ph(CH.sub.2).sub.2                                                                          CHCH  116-118                                                                             377                                   255   1 4-FPh    Ph(CH.sub.2).sub.3                                                                          CHCH  105-108                                                                             391                                   256   1 4-FPh    PhCHCHCH.sub.2                                                                              CHCH  oil  389                                   257   1 4-FPh    s-Bu         CHCH  oil  329                                   258   2 4-FPh    H            CHCH  104-105                                                                             287                                   259   2 (4-FPh)CH.sub.2                                                                         H            CHCH  78-79                                                                               301                                   __________________________________________________________________________

EXAMPLE 17 (E)-3-[2-(4-Fluorophenyl)-2,4,5,6-tetrahydrobenzo[6,7]cyclohepta-[1,2-c]pyrazol-3-yl]-2-propen-1-ol (CP 260, RS step q)

1-Benzosuberone (25 mmol, 4.10 g, 3.74 mL) was added dropwise under N₂ to a stirring suspension of 4.23 g (26 mmol) of 4-fluorophenylhydrazine•HCl and 2.13 g (26 mmol) of NaOAc in 15 mL of absolute EtOH. The mixture was refluxed for 3 h and allowed to stir at room temperature overnight. After concentration, the residue was partitioned between water and Et₂ O. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂ SO₄, and concentrated to give 6.68 g of crude hydrazone as an orange solid. The crude product was dissolved in 25 mL of THF and added dropwise under N₂ to a solution of LDA (made by adding 7.34 mL (52.3 mmol, 5.29 g) of diisopropylamine in 20 mL of THF to 33.7 mL (52.3 mmol) of 1.6M n-BuLi in hexanes) at -10° C. The resulting dark brown solution was stirred for 30 min and was treated with a solution of methyl 4-tetrahydropyranyloxy-2-butenoate (Harnish, W.; Morera, E.; Ortar, G. J. Org. Chem., 1985, 50, 1990-2) in 5 mL of THF. After 1.5 h, 42 mL of 3N aqueous HCl was added to the cold solution, which was then refluxed for 15 min. Et₂ O (150 mL) was added and the organic layer was washed with saturated aqueous NaHCO₃ and brine. After drying over Na₂ SO₄, the mixture was concentrated to give 12 g of light brown oil. The crude residue was refluxed under N₂ for 8 h with 0.31 g (1.25 mmol) of pyrdinium p-toluenesulfonate in 50 mL of MeOH. The solution was concentrated and the residue was partitioned between Et₂ O and water. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂ SO₄, and concentrated to give 9.2 g of brown oil. Purification by MPLC using 1:3 EtOAc:hexanes afforded 3.35 g of yellow solid which was recrystallized from EtOAc:hexanes to give 3.00 g (36%) of the title compound as a white solid, m.p. 127°-128° C.; ¹ H NMR (CDCl₃, 300 MHz) 2.15 (m, 2), 2.84 (m, 4), 4.30 (m, 2), 6.16 (dt, 1, J=16, 5 Hz), 6.44 (d, 1, J=16 Hz), 7.2 (complex, 5), 7.50 (m, 2), 8.07 (m, 1); IR (KBr) 3300 (broad), 1515, 1223 cm⁻¹ ; MS (DCI) m/z 335 (base), 317. Anal. Calcd. for C₂₁ H₁₉ FN₂ O: C, 75.43; H, 5.73; N, 8.38. Found: C, 75.26; H, 5.52; N, 8.24.

EXAMPLE 18 (E)-3-[4,5-Dihydro-2-(4-fluorophenyl)-2H-benz[g]indazol-3-yl]-2-propen-1-ol (CP 261, RS step q)

α-Tetralone (25 mmol, 3.65 g, 3.33 mL) was added dropwise under N₂ to a stirring suspension of 4.23 g (26 mmol) of 4-fluorophenylhydrazine•HCl and 2.13 g (26 mmol) of NaOAc in 15 mL of absolute EtOH. The mixture was refluxed for 2 h, cooled, and concentrated to remove the solvent. The residue was partitioned between water and Et₂ O. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂ SO₄, and concentrated to give 6.21 g of crude hydrazone as a yellow solid. The crude product was dissolved in 30 mL of THF and added dropwise under N₂ to a solution of LDA (made by adding 7.18 mL (51.2 mmol, 5.18 g) of diisopropylamine in 10 mL of THF to 33.0 mL (51.2 mmol) of 1.55M n-BuLi in hexanes) at -10° C. The resulting dark brown solution was stirred for 30 min and was treated with a solution of methyl 4-tetrahydropyranyloxy-2-butenoate (Harnish, W.; Morera, E.; Ortar, G. J. Org. Chem., 1985, 50, 1990-2) in 15 mL of THF. After 1.5 h, 42 mL of 3N aqueous HCl was added to the cold solution, which was then refluxed for 1 h. Et₂ O (150 mL) was added and the organic layer was washed with saturated aqueous NaHCO₃ and brine. After drying over Na₂ SO₄, the mixture was concentrated to give 10.2 g of a light brown oil. The crude residue was refluxed under N₂ for 8 h with 0.31 g (1.25 mmol) of pyrdinium p-toluenesulfonate in 50 mL of MeOH. The solution was concentrated and the residue was partitioned between Et₂ O and water. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over Na₂ SO₄, and concentrated to give 8.44 g of a brown oil. Purification by MPLC using 1:3 EtOAc:hexanes afforded 3.03 g of an off-white solid which was recrystallized from EtOAc:hexanes to give 2.37 g (37%) of the title compound as an off-white solid, m.p. 149°-150° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.70 (t, 1, J=6 Hz), 2.91 (m, 2), 3.02 (m, 2), 4.31 (dt, 2, J=1.5, 4.5 Hz), 6.21 (dt, 1, J=16, 5 Hz), 6.46 (dd, 1, J=1.5, 16 Hz), 7.18 (t, 2, J=8.5 Hz), 7.25 (m, 3), 7.48 (dd, 2, J=5, 8.5 Hz), 7.92 (m, 1); IR (KBr) 3300 (broad), 1509, 1221 cm⁻¹ ; MS (DCI) m/z 321 (base), 303. Anal. Calcd. for C₂₀ H₁₇ FN₂ O: C, 74.98; H, 5.35; N, 8.74. Found: C, 74.78; H, 5.33; N, 8.97.

EXAMPLE 19 (E)-3-[2-(4-Fluorophenyl)-7-benzyl-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-propenal (CP 262, RS step r)

MnO₂ (30 mmol, 2.20 g) was added in one portion to a stirring suspension of 0.84 g (2.32 mmol) of Compound 228 in 15 mL of benzene. The mixture was refluxed gently under N₂ for 3 h. After cooling, the slurry was filtered through a Celite pad and the solids were washed with 100 mL of CH₂ Cl₂. The filtrate was concentrated to give 0.75 g of a yellow solid which was purified by MPLC (1:8 EtOAc:hexanes) to provide 0.529 g (63%) of the title compound as a pale yellow solid, m.p. 130°-131° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.6-2.1 (complex, 4), 2.6-2.8 (complex, 3), 3.10 (m, 1), 3.54 (dd, 1, J=4, 13.5 Hz), 6.48 (dd, 1, J=7.5, 16 Hz), 7.1-7.5 (complex, 10), 9.52 (d, 1, J=7.5 Hz); IR (KBr) 1677, 1617, 1512 cm⁻¹ ; MS (DCI) m/z 361 (base), 307, 269, 241, 178. Anal. Calcd. for C₂₃ H₂₁ FN₂ O: C, 76.65; H, 5.87; N, 7.77. Found: C, 76.47; H, 5.61; N, 7.35.

General procedure for the preparation of 3-substituted 2-propenals shown in Tables 12A and 12B. RS step r:

Method A: MnO₂ (100-120 mmol) was added in one portion to a stirring suspension of 10 mmol of the appropriately substituted alcohol from Table 11A or 11B or Example 17 or 18 in benzene (60 mL). The mixture was refluxed gently under N₂ until TLC analysis indicated that the starting material was completely consumed. After cooling, the slurry was filtered through a Celite pad and the black solids were washed with 250 mL of CH₂ Cl₂. The filtrate was concentrated and the crude product was purified by MPLC or recrystallization.

Method B: CrO₃ (60 mmol) was added under N₂ in several portions to an ice-cold solution of 120 mmol of pyridine in 100 mL of CH₂ Cl₂. The mixture was stirred at room temperature for 15 min and was re-cooled to 0° C. The appropriately substituted alcohol from Table 11A or 11B was either dissolved in a minimum amount of CH₂ Cl₂ and added dropwise or, if solid, was added in 5-10 portions over a 30 min period. The slurry was stirred 30-45 min at 0° C. and was allowed to stir at room temperature until TLC analysis indicated the reaction was complete. Et₂ O (200 mL) was added and the solvent was decanted from the tarry residue through a Celite pad. The residue was sonicated with two 100 mL portions of Et₂ O, which were also decanted through Celite. The combined filtrates were washed successively with 100 mL of 1N aqueous HCl, 100 mL of water, two 100 mL portions of saturated aqueous NaHCO₃, and brine. The ethereal solution was dried (Na₂ SO₄), concentrated, and purified by MPLC or recrystallization.

                                      TABLE 12A                                    __________________________________________________________________________      ##STR30##                                                                     Compound                              Mass Spectrum                            Number                                                                               Method                                                                              n R.sub.1  R.sub.2    mp (°C.)                                                                     m/z [M + H].sup.+                        __________________________________________________________________________     263   B    0 4-FPh    H          138-139                                                                             257                                      264   A    1 4-FPh    (4-FPh)CH.sub.2                                                                           133-136                                                                             379                                      265   A    1 4-FPh    c-Hex      foam 353                                      266   A    1 4-FPh    Et         118-121                                                                             299                                      267   A    1 4-FPh    Me         oil  285                                      268   A    1 4-FPh    PhCHCHCH.sub.2                                                                            foam 387                                      269   A    2 (4-FPh)CH.sub.2                                                                         H          oil  299                                      __________________________________________________________________________

                                      TABLE 12B                                    __________________________________________________________________________      ##STR31##                                                                                                                     Mass                                                                           Spectrum                       Compound                                        m/z                            Number                                                                               Method                                                                              n R.sub.1  R.sub.2      R.sub.3                                                                          Y     mp (°C.)                                                                     [M + H].sup.+                  __________________________________________________________________________     270   B    0 4-FPh    H            H CHCH  127-128                                                                             257                            271   A    1 4-FPh    (2-ClPh)CH.sub.2                                                                            H CHCH  184-185                                                                             395                            272   A    1 4-FPh    (2-Et)Bu     H CHCH   98-100                                                                             355                            273   A    1 4-FPh    (2-Nap)CH.sub.2                                                                             H CHCH  174-175                                                                             411                            274   A    1 4-FPh    (3-MeOPh)CH.sub.2                                                                           H CHCH  97-99                                                                               391                            275   A    1 4-FPh    (3,4-di-MeOPh)CH.sub.2                                                                      H CHCH  foam 421                            276   A    1 4-FPh    (4-ClPh)CH.sub.2                                                                            H CHCH  144-145                                                                             395                            277   A    1 4-FPh    (4-FPh)CH.sub.2                                                                             H CHCH  oil  379                            278   A    1 4-FPh    (4-MePh)CH.sub.2                                                                            H CHCH  160-162                                                                             375                            279   A    1 4-FPh    (4-MeOPh)CH.sub.2                                                                           H CHCH  141-142                                                                             391                            280   A    1 4-FPh    (4-t-BuPh)CH.sub.2                                                                          H CHCH  145-148                                                                             417                            281   A    1 4-FPh                                                             6,7-Benzo-                           CHCH  foam 319                            282   A    1 4-FPh    c-Hex        H CHCH  oil  353                            283   A    1 4-FPh    Et           H CHCH   99-101                                                                             299                            284   B    1 4-ClPh   H            H CHCH  133-134                                                                             287                            285   B    1 4-FPh    H            H CHCH  122-123                                                                             271                            286   A    1 4-FPh    H            H CHC(Me)                                                                              172-173                                                                             285                            287   A    1 4-FPh    Me           H CHCH  145-146                                                                             285                            288   A    1 4-FPh    n-Pr         H CHCH  92-93                                                                               313                            289   A    1 4-FPh    Ph(CH.sub.2).sub.2                                                                          H CHCH  132-134                                                                             375                            290   A    1 4-F Ph   Ph(CH.sub.2).sub.3                                                                          H CHCH  oil  389                            291   A    1 4-FPh    PhCHCHCH.sub.2                                                                              H CHCH  foam 387                            292   A    1 4-FPh    s-Bu         H CHCH  oil  327                            293   A    2 4-FPh                                                             7,8-Benzo-                           CHCH  208-210                                                                             333                            294   A    2 4-FPh    H            H CHCH  92-93                                                                               285                            295   A    2 (4-FPh)CH.sub.2                                                                         H            H CHCH  oil  299                            __________________________________________________________________________

EXAMPLE 20 Ethyl (E)-(3RS,5SR)-7-[7-benzyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5-dihydroxy-6-heptenoate (CP 47, RS step s)

A solution of 1.11 mL of ethyl acetoacetate (8.72 mmol, 1.13 g) in 10 mL of THF was added dropwise under N₂ to a stirring suspension of 0.220 g (9.16 mmol) of oil-free NaH in 10 mL of THF. The mixture was stirred for 30 min and cooled to -10° C. in an ice/acetone bath. n-BuLi in hexanes (1.6M, 8.72 mmol, 5.45 mL) was added slowly, producing a pale yellow solution. After 30 min, a solution of 2.86 g (7.93 mmol) of Compound 262 in 25 mL of THF was added and the resulting yellow solution was stirred for 45 min. Saturated aqueous NH₄ Cl (50 mL) was added and the mixture was extracted with 100 mL of Et₂ O. The organic solution was washed with brine, dried over Na₂ SO₄, and concentrated to give 3.84 g of crude hydroxy keto ester as an orange oil.

The crude intermediate was dissolved in 8 mL of MeOH and 25 mL of THF. A 1.0M solution of Et₃ B in THF (8.60 mmol, 8.60 mL) was added and 20 mL of air was bubbled into the solution via syringe. The solution was stirred under N₂ for 2 h and was cooled to -78° C. NaBH₄ (8.60 mmol, 0.33 g) was added in one portion. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH₄ Cl (100 mL) was added and the mixture was extracted with 150 mL of Et₂ O. The organic solution was washed with brine, dried over Na₂ SO₄, and concentrated to give an oil which was dissolved in 50 mL of MeOH and stirred vigorously under air overnight. The solution was concentrated to give 3.86 g of a yellow oil. Purification by MPLC using 2:3 EtOAc:hexanes yielded 1.83 g (47%) of the title compound as a white foam; ¹ H NMR (CDCl₃, 300 MHz) 1.27 (t, 3, J=7 Hz), 1.3-2.0 (complex, 6), 2.48 (d, 2, J=6 Hz), 2.60 (m, 3), 3.03 (m, 1), 3.55 (m, 1), 3.63 (s, 1), 3.78 (s, 1), 4.17 (q, 2, J=7 Hz), 4.30 (m, 1), 4.50 (m, 1), 6.00 (dd, 1, J=6, 16 Hz), 6.44 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); ¹³ C NMR (CDCl₃, 75 MHz) 14.2, 21.6, 22.8, 27.8, 36.2, 40.7, 41.5, 42.7, 60.9, 68.4, 72.5, 115.7, 116.0 (J_(C-F) =23 Hz), 117.9, 125.9, 127.3 (J_(C-F) =8 Hz), 128.2, 129.3, 135.0, 135.4, 136.2, 140.6, 153.3, 161.8 (J_(C-F) =247 Hz), 172.5; IR (KBr) 3400 (broad), 1732, 1514 cm⁻¹ ; MS (DCI) m/z 493, 457, 401, 333, 241, 91 (base). Anal. Calcd. for C₂₉ H₃₃ FN₂ O₄ : C, 70.71; H, 6.75; N, 5.69. Found: C, 70.90; H, 7.04; N, 5.67.

General procedure for the preparation of 7-substituted (E)-(3RS,5SR)-3,5-dihydroxy-6-heptenoates shown in Tables 13A and 13B (RS step s):

A solution of 11 mmol of ethyl acetoacetate in 10 mL of THF was added dropwise under N₂ to a stirring suspension of 11.5 mmol of oil-free NaH in 15 mL of THF. The mixture was stirred for 30 min and cooled to -10° C. in an ice/acetone bath. n-BuLi in hexanes (11 mmol of a 1.6M solution) was added slowly, producing a pale yellow solution. After 30 min, a solution of 10 mmol of the appropriately substituted aldehyde from Table 12A or 12B in 30 mL of THF was added and the resulting yellow solution was stirred for about 1 h. Saturated aqueous NH₄ Cl (75 mL) was added and the mixture was extracted with 150 mL of Et₂ O. The organic solution was washed with brine, dried over Na₂ SO₄, and concentrated to give the crude hydroxy keto ester which was carried on without purification.

The crude intermediate was dissolved in 10 mL of MeOH and 30 mL of THF. A 1.0M solution of Et₃ B in THF (11 mmol) was added and 20 mL of air was bubbled into the solution via syringe. The solution was stirred under N₂ for 2 h and was cooled to -78° C. NaBH₄ (11 mmol) was added in one portion, causing some gas evolution. The mixture was allowed to warm slowly to room temperature and was stirred overnight. Saturated aqueous NH₄ Cl (150 mL) was added and the mixture was extracted with 200 mL of Et₂ O. The organic solution was washed with brine, dried over Na₂ SO₄, and concentrated. The residue, which smelled of excess Et₃ B, was then dissolved in MeOH and stirred vigorously under air until TLC analysis showed complete conversion of the boron intermediates to the desired product (4-24 h). The MeOH was removed by rotary evaporation and the crude material was purified by MPLC.

                                      TABLE 13A                                    __________________________________________________________________________      ##STR32##                                                                     Compound                        Mass Spectrum                                  Compound                                                                              n  R.sub.1   R.sub.2     m/z [M + H].sup.+                              __________________________________________________________________________     48     0  4-FPh     H           389                                            49     1  4-FPh     (4-FPh)CH.sub.2                                                                            511                                            50     1  4-FPh     c-Hex       485                                            51     1  4-FPh     Et          431                                            52     1  4-FPh     Me          417                                            53     1  4-FPh     PhCHCHCH.sub.2                                                                             515                                            54     2  (4-FPh)CH.sub.2                                                                          H           431                                            __________________________________________________________________________

                                      TABLE 13B                                    __________________________________________________________________________      ##STR33##                                                                     Compound                              Mass Spectrum                            Number                                                                               n R.sub.1  R.sub.2      R.sub.3                                                                          Y     m/z [M + H].sup.+                        __________________________________________________________________________     55    0 4-FPh    H            H CHCH  389                                      56    1 4-FPh    (2-ClPh)CH.sub.2                                                                            H CHCH  528                                      57    1 4-FPh    (2-Et)Bu     H CHCH  487                                      58    1 4-FPh    (3-MeOPh)CH.sub.2                                                                           H CHCH  523                                      59    1 4-FPh    (3,4-di-MeOPh)CH.sub.2                                                                      H CHCH  553                                      60    1 4-FPh    (4-ClPh)CH.sub.2                                                                            H CHCH  528                                      61    1 4-FPh    (4-FPh)CH.sub.2                                                                             H CHCH  511                                      62    1 4-FPh    (4-MePh)CH.sub.2                                                                            H CHCH  507                                      63    1 4-FPh    (4-MeOPh)CH.sub.2                                                                           H CHCH  523                                      64    1 4-FPh    (4-t-BuPh)CH.sub.2                                                                          H CHCH  549                                      65    1 4-FPh                                                                  6,7-Benzo-                      CHCH  451                                      66    1 4-FPh    c-Hex        H CHCH  485                                      67    1 4-FPh    Et           H CHCH  431                                      68    1 4-ClPh   H            H CHCH  419                                      69    1 4-FPh    H            H CHCH  403                                      70    1 4-FPh    H            H CHCMe 417                                      71    1 4-FPh    Me           H CHCH  417                                      72    1 4-FPh    n-Pr         H CHCH  445                                      73    1 4-FPh    Ph(CH.sub.2).sub.2                                                                          H CHCH  507                                      74    1 4-FPh    Ph(CH.sub.2).sub.3                                                                          H CHCH  521                                      75    1 4-FPh    s-Bu         H CHCH  459                                      76    2 4-FPh                                                                  7,8-Benzo-                      CHCH  465                                      77    2 4-FPh    H            H CHCH  417                                      78    2 (4-FPh)CH.sub.2                                                                         H            H CHCH  431                                      __________________________________________________________________________

EXAMPLE 21 (E)-(4RS,6SR)-6-[2-[7-Benzyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (CP 79, RS step w)

A 5.0 mL (1.25 mmol) portion of 0.25N aqueous NaOH was added slowly to an ice-cold solution of 0.500 g (1.02 mmol) of Compound 47 in 15 mL of methanol. After 15 min, the solution was allowed to warm to room temperature and was stirred for 1 h. The solution was concentrated to dryness using a rotary evaporator and was mixed with 50 mL of water and 100 mL of CH₂ Cl₂. The mixture was acidified to pH 2-3 with aqueous 1N HCl. The aqueous layer was extracted with 50 mL of CH₂ Cl₂ and the combined organic layers were washed with brine, dried over Na₂ SO₄, and concentrated. The crude dihydroxy acid (0.49 g) was dissolved in 12 mL of CH₂ Cl₂ and cooled in an ice bath. 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1.07 mmol, 0.455 g) was added in one portion and the mixture was allowed to warm slowly to room temperature and was stirred overnight. EtOAc (100 mL) was added and the white solids were removed by suction filtration. The solids were washed with more EtOAc and the combined filtrates were washed with water and brine and dried (Na₂ SO₄). The solution was concentrated to give 0.60 g of crude product which was purified by MPLC (1:1 EtOAc:hexanes) to provide 0.29 g (64%) of the title compound as a white solid, m.p. 185°-187° C.; ¹ H NMR (CDCl₃, 300 MHz) 1.4-2.1 (complex, 6), 2.21 (d, 1, J=2.5 Hz), 2.62 (m, 4), 2.74 (dd, 1, J=4.5, 18 Hz), 3.06 (m, 1), 3.53 (dt, 1, J=13.5, 3.5), 4.40 (m, 1), 5.25 (m, 1), 6.01 (dd, 1, J=6.5, 16 Hz), 6.49 (d, 1, J=16 Hz), 7.1-7.5 (complex, 9); IR (KBr) 3300 (broad), 1741, 1513 cm⁻¹ ; MS (DCI) m/z 447, 429, 385 (base), 359. Anal. Calcd. for C₂₇ H₂₇ FN₂ O₃ : C, 72.63; H, 6.09; N, 6.27. Found: C, 72.61; H, 6.10; N, 5.97.

General procedure for the preparation of 6-substituted (E)-(4RS,6SR)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones shown in Table 14, RS step w

A 5.0 mL (1.25 mmol) portion of 0.25N aqueous NaOH was added slowly to an ice-cold solution of 1.02 mmol of the appropriately substituted ester from Table 8, 13A, or 13B in methanol (15 mL). After 15 min, the solution was allowed to warm to room temperature and was stirred for 1 h. The solution was concentrated to dryness using a rotary evaporator and was mixed with 50 mL of water and 100 mL of CH₂ Cl₂. The mixture was acidified to pH 2-3 with aqueous 1N HCl. The aqueous layer was extracted with 50 mL of CH₂ Cl₂ and the combined organic layers were washed with brine, dried over Na₂ SO₄, and concentrated. The crude dihydroxy acid was dissolved in 12 mL of CH₂ Cl₂ and cooled in an ice bath. 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1.1 mmol) was added in one portion and the mixture was allowed to warm slowly to room temperature and was stirred overnight. EtOAc (100 mL) was added and the white solids were removed by suction filtration. The solids were washed with more EtOAc and the combined filtrates were washed with water and brine and dried (Na₂ SO₄). The solution was concentrated and the crude product was purified by MPLC.

                  TABLE 14                                                         ______________________________________                                          ##STR34##                                                                     Compound                        Mass Spectrum                                  Number  R.sub.2        mp (°C.)                                                                         m/z [M + H].sup.+                              ______________________________________                                         80      (2-Et)Bu       foam     441                                            81      (2-Nap)CH.sub.2                                                                               foam     497                                            82      (4-t-BuPh)CH.sub.2                                                                            foam     503                                            83      H              foam     357                                            ______________________________________                                     

We claim:
 1. A compound of the formula X: ##STR35## wherein R₁ is selected from any one of H, alkyl, aryl, or substituted aryl; wherein R₂ is selected from any one of alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, aralkenyl, or cycloalkyl;wherein R₃ is H; or wherein R₂ and R₃ may be taken together to form a benzo or naphtho ring system; wherein n=0 to 3 and p=0 to 3 and pharmaceutically acceptable acid salts thereof. 